Antiviral compounds

ABSTRACT

Disclosed herein are new antiviral compounds, together with pharmaceutical compositions that include one or more antiviral compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds. Examples of paramyxovirus infection include an infection caused by human respiratory syncytial virus (RSV).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/165,865, filed Oct. 19, 2018, which is acontinuation application of U.S. patent application Ser. No. 15/678,901,filed Aug. 16, 2017, which is a continuation application of U.S. patentapplication Ser. No. 14/462,937, filed Aug. 19, 2014, which claimspriority benefit of U.S. Provisional Application Nos. 61/945,048, filedFeb. 26, 2014, and 61/868,519, filed Aug. 21, 2013, the disclosures ofeach of which are hereby incorporated by reference in their entiretiesfor all purposes.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing (file name: 756982000903SEQLIST.TXT,date recorded: Mar. 22, 2021, size: 2 KB).

BACKGROUND Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are new antiviralcompounds, together with pharmaceutical compositions, and methods ofsynthesizing the same. Also disclosed herein are methods of amelioratingand/or treating a paramyxovirus viral infection with one or more smallmolecule compounds.

Description

Respiratory viral infections, including upper and lower respiratorytract viral infections, are a leading cause of death of millions ofpeople each year. Upper respiratory tract viral infections involve thenose, sinuses, pharynx and/or larynx. Lower respiratory tract viralinfections involve the respiratory system below the vocal cords,including the trachea, primary bronchi and lungs. Human respiratorysyncytial virus (RSV) is a common cause of respiratory tract infections.Up to 60% of human infants are infected with RSV within their first yearof life. Children and adults are also infected with RSV, where it isoften manifesting as a lower respiratory tract infection with possiblecomplications of bronchiolitis. RSV infections can be particularlysevere in infants and elderly patients. RSV is a negative-sense,single-stranded RNA virus classified within the Paramyxoviridae family,which also includes viruses that cause Newcastle disease, parainfluenza,mumps, measles, and canine distemper.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a paramyxovirus viral infection that can includeadministering to a subject suffering from the paramyxovirus viralinfection an effective amount of one or more compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating a paramyxovirus viralinfection. Still other embodiments described herein relate to compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, that canbe used for ameliorating and/or treating a paramyxovirus viralinfection. Yet still other embodiments disclosed herein relate to amethod of ameliorating and/or treating a paramyxovirus viral infectionthat can include contacting a cell infected with the paramyxovirus withan effective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Some embodiments disclosedherein relate to a method of inhibiting the replication of aparamyxovirus that can include contacting a cell infected with theparamyxovirus with an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof. For example,the paramyxovirus viral infection can be caused by a henipavirus, amorbillivirus, a respirovirus, a rubulavirus, a pneumovirus (including arespiratory syncytial viral infection), a metapneumovirus, hendravirus,nipahvirus, measles, sendai virus, mumps, a human parainfluenza virus(HPIV-1, HPIV-2, HPIV-3 and HPIV-4) and/or a metapneumovirus.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a paramyxovirus viral infection that can includeadministering to a subject suffering from the viral infection aneffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof (for example, one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes one or more compounds described herein, incombination with one or more agents described herein. Some embodimentsdisclosed herein relate to a method of ameliorating and/or treating aparamyxovirus viral infection that can include contacting a cellinfected with the paramyxovirus with an effective amount of a compounddescribed herein or a pharmaceutically acceptable salt thereof (forexample, one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof), or a pharmaceutical composition that includesone or more compounds described herein, in combination with one or moreagents described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A, FIG. 1B, FIG. 1C, FIG. 1D, FIG. 1E, FIG. 1F, FIG. 1G, FIG. 1H,and FIG. 1I show examples of additional agents.

DETAILED DESCRIPTION

Paramyxoviridae family is a family of single stranded RNA viruses.Several genera of the paramyxoviridae family include henipavirus,morbillivirus, respirovirus, rubulavirus, pneumovirus andmetapneumovirus. These viruses can be transmitted person to person viadirect or close contact with contaminated respiratory droplets orfomites. Species of henipavirus include hendravirus and nipahvirus. Aspecies of morbillivirus is measles. Species of respirovirus includesendai virus and human parainfluenza viruses 1 and 3; and species ofrubulavirus include mumps virus and human parainfluenza viruses 2 and 4.A species of metapneumovirus is human metapneumovirus.

Human Respiratory Syncytial Virus (RSV), a species of pneumovirus, cancause respiratory infections, and can be associated with bronchiolitisand pneumonia. Symptoms of an RSV infection include coughing, sneezing,runny nose, fever, decrease in appetite, and wheezing. RSV is the mostcommon cause of bronchiolitis and pneumonia in children under one yearof age in the world, and can be the cause of tracheobronchitis in olderchildren and adults. In the United States, between 75,000 and 125,000infants are hospitalized each year with RSV. Among adults older than 65years of age, an estimated 14,000 deaths and 177,000 hospitalizationshave been attributed to RSV.

Treatment options for people infected with RSV are currently limited.Antibiotics, usually prescribed to treat bacterial infections, andover-the-counter medication are not effective in treating RSV. In severecases, a nebulized bronchodilator, such as albuterol, may be prescribedto relieve some of the symptoms, such as wheezing. RespiGram® (RSV-IGIV,MedImmune, approved for high risk children younger than 24 months ofage), Synagis® (palivizumab, MedImmune, approved for high risk childrenyounger than 24 months of age), and Virzole® (ribavirin by aerosol, ICNpharmaceuticals) have been approved for treatment of RSV.

Symptoms of the measles include fever, cough, runny nose, red eyes and ageneralized rash. Some individuals with measles can develop pneumonia,ear infections and bronchitis. Mumps leads to swelling of the salivaryglands. Symptoms of mumps include fever, loss of appetite and fatigue.Individuals are often immunized against measles and mumps via athree-part MMR vaccine (measles, mumps, and rubella). Humanparainfluenza virus includes four serotypes types, and can cause upperand lower respiratory tract infections. Human parainfluenza virus 1(HPIV-1) can be associated with croup; human parainfluenza virus 3(HPIV-3) can be associated with bronchiolitis and pneumonia. Accordingto the Centers of Disease Control and Prevention (CDC), there are novaccines against human parainfluenza virus.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,R¹⁹, R²⁰, R²¹, R²², R²³, and R^(A) represent substituents that can beattached to the indicated atom. An R group may be substituted orunsubstituted. If two “R” groups are described as being “taken together”the R groups and the atoms they are attached to can form a cycloalkyl,cycloalkenyl, aryl, heteroaryl or heterocycle. For example, withoutlimitation, if R^(a) and R^(b) of an NR^(a)R^(b) group are indicated tobe “taken together,” it means that they are covalently bonded to oneanother to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, acylalkyl, hydroxy, alkoxy, alkoxyalkyl,aminoalkyl, amino acid, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), heterocyclyl(alkyl), hydroxyalkyl, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido,nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, amono-substituted amino group and a di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl,alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s)of the aryl, ring(s) of the heteroaryl or ring(s) of the heteroalicyclylcan contain from “a” to “b”, inclusive, carbon atoms. Thus, for example,a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—,CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated withregard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl,heteroaryl or heteroalicyclyl group, the broadest range described inthese definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds.Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds.Examples of alkynyls include ethynyl and propynyl. An alkynyl group maybe unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein).Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8atoms in the ring(s). When composed of two or more rings, the rings maybe connected together in a fused fashion. A cycloalkenyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one, two, three or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur. The number of atoms in the ring(s) of a heteroarylgroup can vary. For example, the heteroaryl group can contain 4 to 14atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms inthe ring(s). Furthermore, the term “heteroaryl” includes fused ringsystems where two rings, such as at least one aryl ring and at least oneheteroaryl ring, or at least two heteroaryl rings, share at least onechemical bond. Examples of heteroaryl rings include, but are not limitedto, those described herein and the following: furan, furazan, thiophene,benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfur,and nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heterocyclyl may be quaternized.Heterocyclyl or heteroalicyclic groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groupsinclude, but are not limited to, those described herein and thefollowing: 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane,1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin,1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane,tetrahydro-1,4-thiazine, 1,3-thiazinane, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aralkyl may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fusedanalogs.

A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of aheteroalicyclyl(alkyl) may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. Anon-limiting list of alkoxys are methoxy, ethoxy, n-propoxy,1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl)connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substitutedor unsubstituted.

As used herein, “acylalkyl” refers to an acyl connected, as asubstituent, via a lower alkylene group. Examples includearyl-C(═O)—(CH₂)_(n)— and heteroaryl-C(═O)—(CH₂)_(n)—, where n is aninteger in the range of 1 to 6.

As used herein, “alkoxyalkyl” refers to an alkoxy group connected, as asubstituent, via a lower alkylene group. Examples include C₁₋₄alkyl-O—(CH₂)_(n)—, wherein n is an integer in the range of 1 to 6.

As used herein, “aminoalkyl” refers to an optionally substituted aminogroup connected, as a substituent, via a lower alkylene group. Examplesinclude H₂N(CH₂)_(n)—, wherein n is an integer in the range of 1 to 6.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxy ethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxy ethyl. Ahydroxyalkyl may be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl and2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloro-fluoroalkyl, chloro-difluoroalkoxy and2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substitutedor unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as definedherein. An O-carboxy may be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein each X is a halogen, and R_(A) hydrogen, an alkyl, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl).

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An S-sulfonamido may be substituted orunsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-sulfonamido may be substituted orunsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, an alkyl, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-thiocarbamyl may be substituted orunsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-thiocarbamyl may be substituted orunsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

A “urea” group refers to “N(R)—C(═O)—NR_(A)R_(B) group in which R can behydrogen or an alkyl, and R_(A) and R_(B) can be independently hydrogen,an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). A urea may be substituted orunsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

As used herein, “

” indicates a single or double bond, unless stated otherwise.

The term “interferon” is used herein as is commonly understood by one ofordinary skill in the art. Several types of interferons are known tothose skilled in the art, such as Type I interferons, Type 2 interferonsand Type 3 interferons. A non-limiting list of examples include:alpha-interferons, beta-interferons, delta-interferons, gammainterferons, lambda interferons, omega-interferons, tau-interferons,x-interferons, consensus interferons and asialo-interferons. Interferonscan be pegylated. Examples of type 1 interferons include interferonalpha 1A, interferon alpha 1B, interferon alpha 2A, interferon alpha 2B,pegylated-interferon alpha 2a (PEGASYS, Roche), recombinant interferonalpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX, Aradigm),pegylated-interferon alpha 2b (ALBUFERON, Human GenomeSciences/Novartis, PEGINTRON, Schering), recombinant interferon alpha 2b(INTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON,Schering, VIRAFERONPEG, Schering), interferon beta-1a (REBIF, Serono,Inc. and Pfizer), consensus interferon alpha (INFERGEN, ValeantPharmaceutical). Examples of type 2 interferons include interferon gamma1, interferon gamma 2 and pegylated interferon gamma; and examples oftype 3 interferons include interferon lambda 1, interferon lambda 2 andinterferon lambda 3.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

As used herein, the term “amino acid” refers to any amino acid (bothstandard and non-standard amino acids), including, but not limited to,α-amino acids, β-amino acids, γ-amino acids and 5-amino acids. Examplesof suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. Additionalexamples of suitable amino acids include, but are not limited to,ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine. As used herein, “amino acid” alsoincludes amino acids wherein the main-chain carboxylic acid group hasbeen converted to an ester group.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-/iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes, and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds Formula (I)

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof, having the structure:

A-L-Y  (I)

wherein: L can be selected from:

A can be selected from an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₂ alkyl), an optionally substitutedheteroaryl and an optionally substituted heterocyclyl; Y can be selectedfrom an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl and an optionally substituted heterocyclyl; R^(1a), R^(1b),R^(1c) and R^(1d) can be each independently hydrogen or an unsubstitutedC₁₋₄ alkyl; R^(2a), R^(2a1), R^(2b), R^(2b1), R^(2c), R^(2c1), R^(2d)and R^(2d1) can be each independently selected from hydrogen, anoptionally substituted C₁₋₄ alkyl, an optionally substituted aryl(C₁₋₆alkyl), an optionally substituted heterocyclyl(C₁₋₆ alkyl), analkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or R^(2a1) canbe hydrogen, and R^(1a) and R^(2a) can be joined together with the atomsto which they are attached to form an optionally substituted 5 memberedheterocyclyl or an optionally substituted 6 membered heterocyclyl,R^(2b1) can be hydrogen, and R^(1b) and R^(2b) can be joined togetherwith the atoms to which they are attached to form an optionallysubstituted 5 membered heterocyclyl or an optionally substituted 6membered heterocyclyl;

between X^(1a) and X^(2a) represents a single or double bond betweenX^(1a) and X^(2a);

between X^(2a) and X^(3a) represents a single or double bond betweenX^(2a) and X^(3a); provided that

between X^(1a) and X^(2a) and

between X^(2a) and X^(3a) cannot be both double bonds and at least oneof

is a double bond; when

between X^(1a) and X^(2a) represents a double bond and

between X^(2a) and X^(3a) is a single bond, then X^(1a) can be N(nitrogen) or CR^(4a1), X^(2a) can be N (nitrogen) or CR^(5a) and X^(3a)can be NR^(6a1), C(═O) or CR^(6a2)R^(6a3); and when

between X^(1a) and X^(2a) represents a single bond and

between X^(2a) and X^(3a) is a double bond, then X^(1a) can be NR^(4a)or CR^(4a2)R^(4a3), X^(2a) can be N (nitrogen) or CR^(5a) and X^(3a) canbe N (nitrogen) or CR^(6a); or X^(1a), X^(2a) and X^(3a) can be eachindependently C (carbon), N (nitrogen), O (oxygen) or C(═O), and form aring or ring system selected from an optionally substituted aryl, anoptionally substituted heteroaryl and an optionally substitutedheterocyclyl by joining X^(1a) and X^(3a) together; with the provisothat the valencies of X^(1a), X^(2a) and X^(3a) can be eachindependently satisfied with a substituent selected from hydrogen and anoptionally substituted C₁₋₄ alkyl, and X^(1a), X^(2a) and X^(3a) areuncharged; R^(3a) and R^(3a1) can be each independently selected fromhydrogen, hydroxy, halogen, amino, an optionally substituted C₁₋₄ alkyl,an optionally substituted C₂₋₄ alkenyl, an optionally substituted C₂₋₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₁₋₄ alkoxy, —O-carboxy, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, CHF₂, CF₃ and

provided that R^(3a) and R^(3a1) cannot be both hydrogen; or R^(3a) andR^(3a1) can together form ═N—OR^(a); or R^(3a) and R^(3a1) can togetherwith the atom to which they are attached can be joined to form anoptionally substituted 3 membered ring, an optionally substituted 4membered ring, an optionally substituted 5 membered ring or anoptionally substituted 6 membered ring; R^(4a), R^(4a1), R^(4a2) andR^(4a3) can be each independently hydrogen or an unsubstituted C₁₋₄alkyl; R^(5a) and R^(5a1) can be each independently be hydrogen or anunsubstituted C₁₋₄ alkyl; R^(6a) and R^(6a1) can be each independentlyhydrogen, an optionally substituted C₁₋₄ alkyl or an optionallysubstituted alkoxyalkyl; R^(6a2) and R^(6a3) can be each independentlyhydrogen or an unsubstituted C₁₋₄ alkyl; X^(1b), X^(2b) and X^(3b) canbe each independently C (carbon), N (nitrogen), O (oxygen) or C(═O), andform a bi-cyclic ring selected from an optionally substituted aryl, anoptionally substituted heteroaryl and an optionally substitutedheterocyclyl by joining X^(1b) and X^(3b) together; provided that atleast one of X^(1b), X^(2b) and X^(3b) comprises a nitrogen atom; withthe proviso that the valencies of X^(1b), X^(2b) and X^(3b) can be eachindependently satisfied with a substituent selected from hydrogen and anoptionally substituted C₁₋₄ alkyl, and X^(1b), X^(2b) and X^(3b) areuncharged; R^(3c) and R^(3c1) can be each independently selected fromhydrogen, hydroxy, halogen, amino, an optionally substituted C₁₋₄ alkyl,an optionally substituted C₂₋₄ alkenyl, an optionally substituted C₂₋₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₁₋₄ alkoxy, —O-carboxy, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, CHF₂, CF₃ and

provided that R^(3c) and R^(3c1) cannot be both hydrogen; or R^(3c) andR^(3c1) can together form ═N—OR^(c); or R^(3c) and R^(3c1) can togetherwith the atom to which they are attached can be joined to form anoptionally substituted 3 membered ring, an optionally substituted 4membered ring, an optionally substituted 5 membered ring or anoptionally substituted 6 membered ring; R^(a) and R^(c) can be eachindependently hydrogen or an unsubstituted C₁₋₄ alkyl; R^(4c) and R^(5c)can be taken together to form an unsubstituted aryl, an unsubstitutedheteroaryl or an optionally substituted heterocyclyl; Z^(c) can be N orCH; m^(d) can be 0 or 1; and ring B^(d) can be an optionally substitutedC₅ cycloalkyl; ring B^(d1) can be an optionally substituted pyridinyl;and provided that when L is Formula (He), then Y is absent.

Formula (Ia)

In some embodiments, L can be Formula (Ia):

In some embodiments of Formula (Ia), X^(1a) can be CR^(4a1) orCR^(4a2)R^(4a3), X^(2a) can be N (nitrogen), and X^(3a) can be CR^(6a)or CR^(6a2)R^(6a3). In some embodiments of Formula (Ia),

between X^(1a) and X^(2a) can be a single bond,

between X^(2a) and X^(3a) can be a double bond, X^(1a) can beCR^(4a2)R^(4a3), X^(2a) can be N (nitrogen), and X^(3b) can be CR^(6a).In other embodiments of Formula (Ia),

between X^(1a) and X^(2a) can be a double bond,

between X^(2a) and X^(3a) can be a single bond, X^(1a) can be CR^(4a1),X^(2b) can be N (nitrogen), and X^(3b) can be CR^(6a2)R^(6a3). In someembodiments, including those of this paragraph, R^(5a) can be hydrogen.In some embodiments including those of this paragraph, R^(5a1) can behydrogen. In some embodiments, —X^(1a)

X^(2a)

X^(3a)— can be —CH₂—N═CH— or —CH═N—CH₂—. In other embodiments, —X^(1a)

X^(2a)

X^(3a)— can be —N═N—CH₂—, —N═CH—CH₂— or —N═CH—NH—. In still otherembodiments, —X^(1a)

X^(2a)

X^(3a)— can be —CH₂—CH═N—, —NH—CH═NH— or —NH—N═CH—. In some embodiments,X^(1a), X^(2a) and X^(3a) can be each independently C (carbon), N(nitrogen), O (oxygen) or C(═O), and form a ring or ring system selectedfrom an optionally substituted aryl, an optionally substitutedheteroaryl and an optionally substituted heterocyclyl by joining X^(1a)and X^(3a) together; with the proviso that the valencies of X^(1a),X^(2a) and X^(3a) can be each independently satisfied with a substituentselected from hydrogen and an optionally substituted C₁₋₄ alkyl; andX^(1a), X^(2a) and X^(3a) are uncharged.

Formula (Ia1)

In some embodiments, L of Formula (Ia) can be Formula (Ia1):

wherein: X^(1a), X^(2a) and X^(3a) can be each independently C (carbon),N (nitrogen), O (oxygen) or C(═O), and form a ring or ring systemselected from an optionally substituted aryl, an optionally substitutedheteroaryl and an optionally substituted heterocyclyl by joining X^(1a)and X^(3a) together; with the proviso that the valencies of X^(1a),X^(2a) and X^(3a) can be each independently satisfied with a substituentselected from hydrogen and an optionally substituted C₁₋₄ alkyl; andX^(1a), X^(2a) and X^(3a) are uncharged.

In some embodiments of Formula (Ia1), X^(1a) can be C, X^(2a) can be Nand X^(3a) can be C. In some embodiments of Formula (Ia1),

between X^(1a) and X^(2a) can be a single bond,

between X^(2a) and X^(3a) can be a double bond, X^(1a) can be C, X^(2a)can be N and X^(3a) can be C. In other embodiments of Formula (Ia1),

between X^(1a) and X^(2a) can be a double bond,

between X^(2a) and X^(3a) can be a single bond, X^(1a) can be C, X^(2a)can be N and X^(3a) can be C. In still other embodiments of Formula(Ia1),

between X^(1a) and X^(2a) can be a single bond,

between X^(2a) and X^(3a) can be a single bond, X^(1a) can be C, X^(2a)can be O and X^(3a) can be C. In some embodiments, the valencies ofX^(1a), X^(2a) and X^(3a) can be each independently satisfied withhydrogen or an unsubstituted C₁₋₄ alkyl, such as CH₃.

In some embodiments, the ring or ring system of Formula (Ia1) can be anoptionally substituted aryl. In other embodiments, the ring or ringsystem of Formula (Ia1) can be an optionally substituted mono-cyclicheteroaryl. In still other embodiments, the ring or ring system ofFormula (Ia1) can be an optionally substituted bi-cyclic heteroaryl. Insome embodiments, the ring or ring system of Formula (Ia1) can be anoptionally substituted mono-cyclic heterocyclyl. In some embodiments,the ring or ring system of Formula (Ia1) can be an optionallysubstituted bi-cyclic heterocyclyl.

In some embodiments of Formula (Ia1),

can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

wherein R^(A1), R^(A2), R^(A3) and R^(A4) can be each independentlyhydrogen or an unsubstituted C₁₋₆ alkyl.

In some embodiments,

can be an optionally substituted

In some embodiments,

can be substituted with one or more substituents selected from amino,mono-substituted amino, di-substituted amino, hydroxyalkyl, alkyl andalkoxy. In some embodiments,

can be an unsubstituted

In other embodiments,

can be a substituted

or a substituted

In some embodiments,

can be an optionally substituted

or an optionally substituted

R^(3a) can be hydroxy and R^(3a1) can be selected from amino, anunsubstituted C₁₋₄ alkyl, an unsubstituted C₂₋₄ alkenyl, anunsubstituted C₂₋₄ alkynyl, an unsubstituted C₃₋₆ cycloalkyl (forexample, cyclopropyl), an unsubstituted C₁₋₄ alkoxy (such as OCH₃),hydroxy, halogen and an unsubstituted heteroaryl (for example,thiazole).

In some embodiments, when one of R^(3a) and R^(3a1) is H and the otherof R^(3a) and R^(3a1) is OH, then

is not an unsubstituted

In other embodiments, when one of R^(3a) and R^(3a1) is H, then theother of R^(3a) and R^(3a1) is not OH. In some embodiments,

is not an optionally substituted pyrimidine. In some embodiments, acompound of Formula (I) cannot be

Formula (Ia2)

In some embodiments, L of Formula (Ia) can be Formula (Ia2):

wherein R^(7a1), R^(7a2) and R^(7a3) can be each independently selectedfrom hydrogen, halogen, hydroxy, an optionally substituted C₁₋₈ alkyl,an optionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl, an optionally substituted hydroxyalkyl, anoptionally substituted C₁₋₈ alkoxy, an optionally substitutedalkoxyalkyl, amino, mono-substituted amino, di-substituted amino,halo(C₁₋₈ alkyl), haloalkyl, an optionally substituted O-amido and anoptionally substituted C-carboxy. In some embodiments, R^(7a1) can be anunsubstituted C₁₋₄ alkoxy, and R^(7a2) and R^(7a3) can be both hydrogen.In other embodiments, R^(7a1) can be a substituted C₁₋₄ alkoxy, andR^(7a2) and R^(7a3) can be both hydrogen. For example, R^(7a1) can be asubstituted C₁₋₄ alkoxy substituted with an amino, mono-substitutedamino or a di-substituted amino. In some embodiments, R^(7a1) can behydrogen, R^(7a2) can be an optionally substituted C₁₋₄ alkyl, andR^(7a3) can be hydrogen. In other embodiments, R^(7a1) can be hydrogen,R^(7a2) can be a substituted C₃₋₆ cycloalkyl, and R^(7a3) can behydrogen. In still other embodiments, R^(7a1) can be hydrogen, R^(7a2)can be a mono-substituted amino, and R^(7a3) can be hydrogen. In yetstill other embodiments, R^(7a1) can be a mono-substituted amino or anoptionally substituted O-amido (such as —C(═O)NH₂) and R^(7a2) andR^(7a3) can be both hydrogen. For example, the mono-substituted amino ofR^(7a1) or R^(7a2) can be —N(C₁₋₄ alkyl), such as —NCH₃. In someembodiments, R^(7a1) can be a substituted C₁₋₈ alkyl (such as an aminosubstituted C₁₋₈ alkyl) and R^(7a2) and R^(7a3) can be both hydrogen. Inother embodiments, R^(7a1) and R^(7a2) can be both hydrogen and R^(7a3)can be halogen. In other embodiments, R^(7a1) and R^(7a3) can be bothhydrogen and R^(7a2) can be an optionally substituted heterocyclyl, suchas an optionally substituted mono-cyclic heterocyclyl. Examples ofoptionally substituted mono-cyclic heterocyclyl at R^(7a2) include, butare not limited to, an optionally substituted azetidine, an optionallysubstituted pyrrolidine, an optionally substituted pyrrolidinone, anoptionally substituted piperidine and an optionally substituted oxetane.

When R^(7a1), R^(7a2) and/or R^(7a3) are substituted, possiblesubstituent(s) includes those provided in the list of “substituted”along with urea, amidine and acetylurea. For example, the C₁₋₄ alkyl,C₃₋₆ cycloalkyl and mono-cyclic heterocyclyl of R^(7a2) can besubstituted with various substituent(s), such as, halo, hydroxy, C₁₋₄alkoxy, an optionally substituted aryl(C₁₋₄ alkyl), an optionallysubstituted C-carboxy, amino, an optionally substituted mono-substitutedamino, an optionally substituted di-substituted amino, an optionallysubstituted C-amido, an optionally substituted N-amido, an optionallysubstituted N-carbamyl, an optionally substituted N-sulfonamido, anoptionally substituted urea, an optionally substituted amidine and anoptionally substituted acetylurea (e.g., halogenated acetylurea).Non-limiting examples of substituted C₁₋₄ alkyls and substituted C₃₋₆cycloalkyls of R^(7a2) are as follows:

Formula (Ia3)

In some embodiments, L of Formula (Ia) can be Formula (Ia3):

wherein: the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted cycloalkyl anoptionally substituted aryl, an optionally substituted heteroaryl or anoptionally substituted heterocyclyl; and R^(8a3) can be selected fromhydrogen, halogen, hydroxy, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl, an optionally substituted hydroxyalkyl, anoptionally substituted C₁₋₈ alkoxy, an optionally substitutedalkoxyalkyl, amino, mono-substituted amino, di-substituted amino,halo(C₁₋₈ alkyl), haloalkyl and an optionally substituted C-carboxy.

In some embodiments of Formula (Ia3), the dashed semi-circle along withthe two carbon atoms to which it is connected can form an optionallysubstituted 5-membered cycloalkyl. In other embodiments of Formula(Ia3), the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted 6-memberedcycloalkyl. In still other embodiments of Formula (Ia3), the dashedsemi-circle along with the two carbon atoms to which it is connected canform an optionally substituted aryl (for example, phenyl). In someembodiments of Formula (Ia3), the dashed semi-circle along with the twocarbon atoms to which it is connected can form an optionally substituted5-membered heteroaryl. In other embodiments of Formula (Ia3), the dashedsemi-circle along with the two carbon atoms to which it is connected canform an optionally substituted 6-membered heteroaryl. In still otherembodiments of Formula (Ia3), the dashed semi-circle along with the twocarbon atoms to which it is connected can form an optionally substituted5-membered heterocyclyl. In yet still other embodiments of Formula(Ia3), the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted 6-memberedheterocyclyl.

In some embodiments, the bicyclic ring system can be selected from anoptionally substituted

an optionally substituted

and an optionally substituted

wherein each

can be independently absent or a bond; each R^(A5), each R^(A6), eachR^(A7) can be halogen, an unsubstituted C₁₋₆ alkyl, hydroxy, amino, anoptionally substituted mono-substituted amino, an optionally substituteddi-substituted amino, —(CH₂)₁₋₄OH, —(CH₂)₁₋₄NH₂ or N-sulfmamido (forexample, —NH—S(═O)C₁₋₄ alkyl), or two R^(A5), two R^(A6) or two R^(A7)are taken together to form an optionally substituted 5-membered ring toan optionally substituted 6-membered ring (such as an optionallysubstituted cycloalkyl or an optionally substituted heterocyclyl); andR^(A8) can be hydrogen or an unsubstituted C₁₋₆ alkyl. In someembodiments of this paragraph,

can be absent. In some embodiments of this paragraph,

can be a bond such that a double bond is present between the betweencarbons. In some embodiments, at least two R^(A5) groups can be anunsubstituted C₁₋₆ alkyl (for example, CH₃). In some embodiments, atleast two R^(A6) groups can be an unsubstituted C₁₋₆ alkyl (for example,CH₃). Examples of these bi-cyclic groups include the following:

In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(1a)can be hydrogen. In other embodiments of Formulae (Ia), (Ia1), (Ia2)and/or (Ia3), R^(1a) can be an unsubstituted C₁₋₄ alkyl.

In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), bothR^(2a) and R^(2a1) can be hydrogen. In other embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(2a) can be hydrogen and R^(2a1) canbe an unsubstituted C₁₋₄ alkyl. In still other embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(2a) can be hydrogen and R^(2a1) canbe a substituted C₁₋₄ alkyl. In yet still other embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(2a) can be hydrogen and R^(2a1) canbe an optionally substituted aryl(C₁₋₆ alkyl) or an optionallysubstituted heterocyclyl(C₁₋₆ alkyl). In some embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(2a) can be hydrogen and R^(2a1) canbe an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodimentsof Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(2a) can be hydrogen andR^(2a1) can be hydroxy. In still other embodiments of Formulae (Ia),(Ia1), (Ia2) and/or (Ia3), R^(2a1) can be hydrogen, and R^(1a) andR^(2a) can be joined together with the atoms to which they are attachedto form an optionally substituted 5 membered heterocyclyl (for example,pyrrolidinyl) or an optionally substituted 6 membered heterocyclyl (forexample, piperidinyl). In yet still other embodiments of Formulae (Ia),(Ia1), (Ia2) and/or (Ia3), R^(2a) and R^(2a1) both can be an optionallysubstituted C₁₋₄ alkyl.

In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a)can be hydrogen, and R^(3a1) can be selected from amino, anunsubstituted C₁₋₄ alkyl, an unsubstituted C₂₋₄ alkenyl, anunsubstituted C₂₋₄ alkynyl, an unsubstituted C₃₋₆ cycloalkyl (forexample, cyclopropyl), an unsubstituted C₁₋₄ alkoxy (such as OCH₃), anunsubstituted —O-carboxy (such as —OC(═O)C₁₋₄ alkyl), hydroxy, halogen,an unsubstituted heteroaryl (for example, thiazole) and an optionallysubstituted heterocyclyl (for example, azetidine). In some embodimentsof Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) can be hydrogen, andR^(3a1) can be hydroxy. In other embodiments or Formulae (Ia), (Ia1),(Ia2) and/or (Ia3), R^(3a) and R^(3a1) can be both halogen. In stillother embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a)can be hydrogen, and R^(3a1) can be unsubstituted C₁₋₄ alkyl. In yetstill other embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3),R^(3a) can be hydroxy, and R^(3a1) can be selected from amino, anunsubstituted C₁₋₄ alkyl, an unsubstituted C₂₋₄ alkenyl, anunsubstituted C₂₋₄ alkynyl, an unsubstituted C₃₋₆ cycloalkyl (forexample, cyclopropyl), an unsubstituted C₁₋₄ alkoxy (such as OCH₃),hydroxy, halogen, an unsubstituted heteroaryl (for example, thiazole)and an optionally substituted heterocyclyl (for example, azetidine). Insome embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) canbe hydroxy, and R^(3a1) can be an unsubstituted C₁₋₄ alkyl. In otherembodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) can behydroxy, and R^(3a1) can be an unsubstituted C₂₋₄ alkenyl (such asethenyl or propenyl) or an unsubstituted C₂₋₄ alkynyl (such as ethynylor propynyl). In still other embodiments of Formulae (Ia), (Ia1), (Ia2)and/or (Ia3), R^(3a) can be hydroxy, and R^(3a1) can be CF₃. In yetstill other embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3),R^(3a) can be hydroxy, and R^(3a1) can be CHF₂. In some embodiments ofFormulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) can be halogen, andR^(3a1) can be CF₃ or CHF₂. In other embodiments of Formulae (Ia),(Ia1), (Ia2) and/or (Ia3), R^(3a) can be halogen, and R^(3a1) can beCHF₂. In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3),R^(3a) can be hydroxy, and R^(3a1) can be an unsubstituted C₃₋₆cycloalkyl, for example, an unsubstituted cyclopropyl. In someembodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) can behalogen, and R^(3a1) can be an unsubstituted C₃₋₆ cycloalkyl, forexample, an unsubstituted cyclopropyl. In other embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) can be an unsubstituted C₁₋₄alkoxy (such as methoxy), and R^(3a1) can be an unsubstituted C₁₋₄ alkyl(such as methyl). In still other embodiments of Formulae (Ia), (Ia1),(Ia2) and/or (Ia3), R^(3a) and R^(3a1) can be both an unsubstituted C₁₋₄alkyl, for example, R^(3a) and R^(3a1) can be both methyl. In yet sillother embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), one ofR^(3a) and R^(3a1) can be an optionally substituted mono-cyclicheteroaryl; and the other of R^(3a) and R^(3a1) can be hydroxy. In someembodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), one of R^(3a)and R^(3a1) can be an unsubstituted C₁₋₄ alkyl (such as methyl); and theother of R^(3a) and R^(3a1) can be an unsubstituted —O-carboxy (such as—OC(═O)C₁₋₄ alkyl).

When one of R^(3a) and R^(3a1) is a substituted C₁₋₄ alkyl, the C₁₋₄alkyl can be substituted with various substituents. For example, in someembodiments, one of R^(3a) and R^(3a1) is a substituted C₁₋₄ alkylsubstituted with substituent selected from halogen, hydroxy, amino,mono-substituted amino (for example, —NH(C₁₋₄ alkyl)), di-substitutedamino, —N-amido, mono-cyclic heteroaryl and mono-cyclic heterocyclyl. Insome embodiments, one of R^(3a) and R^(3a1) can be an optionallysubstituted mono-cyclic heteroaryl or an optionally substitutedmono-cyclic heterocyclyl and the other of R^(3a) and R^(3a1) can behydroxy. The mono-cyclic heteroaryl substituted on the C₁₋₄ alkyl of oneof R^(3a) and R^(3a1) can be 5-membered or 6-membered heteroaryl. Themono-cyclic heterocyclyl substituted on the C₁₋₄ alkyl of one of R^(3a)and R^(3a1) can be 4-membered, 5-membered or 6-membered heterocyclyl.For example, one of R^(3a) and R^(3a1) can be a substituted C₁₋₄ alkylsubstituted with substituent selected from an optionally substitutedimidazole, an optionally substituted pyrazole, an optionally substitutedpyrrolidine, an optionally substituted piperidine, an optionallysubstituted piperazine, an optionally substituted morpholine, anoptionally substituted triazole, an optionally substituted piperazinoneand an optionally substituted azetidine.

In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a)and R^(3a1) can together form N═OR^(a). In some embodiments of Formulae(Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a) and R^(3a1) together form N═OH.In other embodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), R^(3a)and R^(3a1) can together form N═OCH₃. In some embodiments of Formulae(la), (Ia1), (Ia2) and/or (Ia3), R^(3a) and R^(3a1) can join togetherwith the atom to which they are attached to form an optionallysubstituted 3 to 6 membered ring. In some embodiments of Formulae (Ia),(Ia1), (Ia2) and/or (Ia3), the 3 to 6 membered ring can be a C₃₋₆cycloalkyl. In other embodiments of Formulae (Ia), (Ia1), (Ia2) and/or(Ia3), the ring can be a 3 to 6 membered heterocyclyl, for example, anoptionally substituted oxetane or an optionally substitutedoxazolidinone. In some embodiments of Formulae (Ia), (Ia1), (Ia2) and/or(Ia3), the carbon to which R^(3a) and R^(3a1) are attached can be achiral center. When the carbon to which R^(3a) and R^(3a1) are attacheda chiral center, in some embodiments of Formulae (Ia), (Ia1), (Ia2)and/or (Ia3), the carbon can have a (Reconfiguration. In otherembodiments of Formulae (Ia), (Ia1), (Ia2) and/or (Ia3), the carbon towhich R^(3a) and R^(3a1) are attached can have a (S)-configuration.

Formula (Ib)

In some embodiments, L of Formula (I) can be Formula (Ib):

wherein the dotted curved line between X^(1b) and X^(3b) indicates abi-cyclic ring selected from an optionally substituted bi-cyclicheteroaryl and an optionally substituted bi-cyclic heterocyclyl byjoining X^(1b) and X^(3b) together, wherein

between X^(1b) and X^(2b) represents a single or double bond betweenX^(1b) and X^(2b);

between X^(2b) and X^(3b) represents a single or double bond betweenX^(2b) and X^(3b); wherein X^(1b), X^(2b) and X^(3b) can be eachindependently C (carbon), N (nitrogen), O (oxygen) or C(═O); andprovided that at least one of X^(1b), X^(2b) and X^(3b) comprises anitrogen atom and both

cannot be double bonds; with the proviso that the valencies of X^(1b),X^(2b) and X^(3b) can be each independently satisfied with a substituentselected from hydrogen and an optionally substituted C₁₋₄ alkyl; andX^(1b), X^(2b) and X^(3b) are uncharged. In some embodiments, thevalencies of X^(1b), X^(2b) and X^(3b) can be each independentlysatisfied with a substituent selected from hydrogen and an unsubstitutedC₁₋₄ alkyl. In some embodiments, the valencies of X^(1b), X^(2b) andX^(3b) can be each independently satisfied with hydrogen or methyl.

In some embodiments of Formula (Ib), the bi-cyclic ring can be anoptionally substituted 9-membered bi-cyclic heteroaryl. In otherembodiments of Formula (Ib), the bi-cyclic ring can be an optionallysubstituted 9-membered bi-cyclic heterocyclyl. In still otherembodiments of Formula (Ib), the bi-cyclic ring can be an optionallysubstituted 10-membered bi-cyclic heteroaryl. In yet still someembodiments of Formula (Ib), the bi-cyclic ring can be an optionallysubstituted 10-membered bi-cyclic heterocyclyl.

In some embodiments of Formula (Ib), X^(1b) can be C, X^(2b) can be Nand X^(3b) can be C. In other embodiments of Formula (Ib), X^(1b) can beN, X^(2b) can be N and X^(3b) can be C. In still other embodiments ofFormula (Ib), X^(1b) can be N, X^(2b) can be C(═O) and X^(3b) can be N.In yet still other embodiments of Formula (Ib), X^(1b) can be C, X^(2b)can be O and X^(3b) can be C.

In some embodiments of Formula (Ib), when X^(1b) can be C, X^(2b) can beN and X^(3b) can be C, the bi-cyclic ring can be an optionallysubstituted bi-cyclic heteroaryl ring. In other embodiments of Formula(Ib), when X^(1b) can be C, X^(2b) can be N and X^(3b) can be C, thebi-cyclic ring can be an optionally substituted bi-cyclic heterocyclylring.

Formula (Ib1)

In some embodiments, L of Formula (Ib) can be Formula (Ib1):

wherein: the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl or anoptionally substituted heterocyclyl; and R^(4b3) can be selected fromhydrogen, halogen, hydroxy, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted heterocyclyl, an optionally substituted hydroxyalkyl, anoptionally substituted C₁₋₈ alkoxy, an optionally substitutedalkoxyalkyl, amino, mono-substituted amino, di-substituted amino,halo(C₁₋₈ alkyl), haloalkyl and an optionally substituted C-carboxy.

In some embodiments of Formula (Ib1), the dashed semi-circle along withthe two carbon atoms to which it is connected can form an optionallysubstituted 5-membered cycloalkenyl. In other embodiments of Formula(Ib1), the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted 6-memberedcycloalkenyl. In still other embodiments of Formula (Ib1), the dashedsemi-circle along with the two carbon atoms to which it is connected canform an optionally substituted aryl (for example, phenyl). In someembodiments of Formula (Ib1), the dashed semi-circle along with the twocarbon atoms to which it is connected can form an optionally substituted5-membered heteroaryl. In other embodiments of Formula (Ib1), the dashedsemi-circle along with the two carbon atoms to which it is connected canform an optionally substituted 6-membered heteroaryl. In still otherembodiments of Formula (Ib1), the dashed semi-circle along with the twocarbon atoms to which it is connected can form an optionally substituted5-membered heterocyclyl. In yet still other embodiments of Formula(Ib1), the dashed semi-circle along with the two carbon atoms to whichit is connected can form an optionally substituted 6-memberedheterocyclyl.

In some embodiments, the bi-cyclic ring system can be selected from anoptionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

wherein each

can be independently absent or a bond; each R^(B1), each R^(B2) and eachR^(B3) can be an unsubstituted C₁₋₆ alkyl, halogen, hydroxy, amino,mono-substituted amino, di-substituted amino or —NH—S(═O)C₁₋₄ alkyl; andR^(B4) can be hydrogen or an unsubstituted C₁₋₆ alkyl. In someembodiments of this paragraph,

can be absent. In some embodiments of this paragraph,

can be a bond such that a double bond is present between the betweencarbons. In some embodiments, at least two R^(B2) groups can be anunsubstituted C₁₋₆ alkyl (for example, CH₃). In some embodiments, atleast two R^(B3) groups can be an unsubstituted C₁₋₆ alkyl (for example,CH₃). Examples of these bi-cyclic groups include the following:

In some embodiments of Formulae (Ib) and (Ib1), R^(1b) can be hydrogen.

In some embodiments of Formulae (Ib) and (Ib1), both R^(2b) and R^(2b1)can be hydrogen. In other embodiments of Formulae (Ib) and (Ib1), R^(2b)can be hydrogen and R^(2b1) can be an unsubstituted C₁₋₄ alkyl. In stillother embodiments of Formulae (Ib) and (Ib1), R^(2b) can be hydrogen andR^(2b1) can be a substituted C₁₋₄ alkyl. In yet still other embodimentsof Formulae (Ib) and (Ib1), R^(2b) can be hydrogen and R^(2b1) can be anoptionally substituted aryl(C₁₋₆ alkyl) or an optionally substitutedheterocyclyl(C₁₋₆ alkyl). In some embodiments of Formulae (Ib) and(Ib1), R^(2b) can be hydrogen and R^(2b1) can be an alkoxyalkyl, anaminoalkyl or a hydroxyalkyl. In other embodiments of Formulae (Ib) and(Ib1), R^(2b) can be hydrogen and R^(2b1) can be hydroxy. In still otherembodiments of Formulae (Ib) and (Ib1), R^(2b1) can be hydrogen, andR^(1b) and R^(2b) can be joined together with the atoms to which theyare attached to form an optionally substituted 5 membered heterocyclylor an optionally substituted 6 membered heterocyclyl.

Formula (Ic)

In some embodiments, L can be Formula (Ic):

In some embodiments of Formula (Ic), R^(1c) can be hydrogen. In otherembodiments of Formula (Ic), R^(1c) can be an unsubstituted C₁₋₄ alkyl.

In some embodiments of Formula (Ic), both R^(2c) and R^(2c1) can behydrogen. In other embodiments of Formula (Ic), R^(2c) can be hydrogenand R^(2c1) can be an unsubstituted C₁₋₄ alkyl. In still otherembodiments of Formula (Ic), R^(2c) can be hydrogen and R^(2c1) can be asubstituted C₁₋₄ alkyl. In yet still other embodiments of Formula (Ic),R^(2c) can be hydrogen and R^(2c1) can be an optionally substitutedaryl(C₁₋₆ alkyl) or an optionally substituted heterocyclyl(C₁₋₆ alkyl).In some embodiments of Formula (Ic), R^(2c) can be hydrogen and R^(2c1)can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In otherembodiments of Formula (Ic), R^(2c) can be hydrogen and R^(2c1) can behydroxy. In still other embodiments of Formula (Ic), R^(2c) and R^(2c1)both can be an optionally substituted C₁₋₄ alkyl.

In some embodiments of Formula (Ic), R^(3c) can be hydrogen, and R^(3c1)can be selected from amino, an unsubstituted C₁₋₄ alkyl, anunsubstituted C₂₋₄ alkenyl, an unsubstituted C₂₋₄ alkynyl, anunsubstituted C₃₋₆ cycloalkyl (for example, cyclopropyl), anunsubstituted C₁₋₄ alkoxy (such as OCH₃), hydroxy, halogen and anunsubstituted heteroaryl (for example, thiazole). In some embodiments,R^(3c) can be hydrogen, and R^(3c1) can be hydroxy. In otherembodiments, R^(3c) and R^(3c1) can be both halogen. In still otherembodiments, R^(3c) can be hydrogen, and R^(3c1) can be unsubstitutedC₁₋₄ alkyl. In yet still other embodiments of Formula (Ic), R^(3c) canbe hydroxy, and R^(3c1) can be selected from amino, an unsubstitutedC₁₋₄ alkyl, an unsubstituted C₂₋₄ alkenyl, an unsubstituted C₂₋₄alkynyl, an unsubstituted C₃₋₆ cycloalkyl (for example, cyclopropyl), anunsubstituted C₁₋₄ alkoxy (such as OCH₃), hydroxy, halogen and anunsubstituted heteroaryl (for example, thiazole). In some embodiments ofFormula (Ic), R^(3c) can be hydroxy, and R^(3c1) can be an unsubstitutedC₁₋₄ alkyl. In some embodiments of Formula (Ic), R^(3c) and R^(3c1) cantogether form N═OR^(c), for example, N═OH or N═OCH₃. In some embodimentsof Formula (Ic), R^(3c) and R^(3c1) can join together with the atom towhich they are attached to form an optionally substituted 3 to 6membered ring. In some embodiments, the 3 to 6 membered ring can be aC₃₋₆ cycloalkyl. In other embodiments, the ring can be a 3 to 6 memberedheterocyclyl, for example, an optionally substituted oxetane. In someembodiments, the carbon to which R^(3c) and R^(3c1) are attached can bea chiral center. When the carbon to which R^(3c) and R^(3c1) areattached a chiral center, in some embodiments, the carbon can have a(R)-configuration. In other embodiments, the carbon to which R^(3c) andR^(3c1) are attached can have a (S)-configuration.

In some embodiments of Formula (Ic), Z^(c) can be N. In some embodimentsof Formula (Ic), Z^(c) can be CH.

In some embodiments of Formula (Ic), R^(4c) and R^(5c) can be takentogether to form an unsubstituted aryl (for example, phenyl). In otherembodiments of Formula (Ic), R^(4c) and R^(5c) can be taken together toform an unsubstituted heteroaryl, such as piperidinyl. In still otherembodiments of Formula (Ic), R^(4c) and R^(5c) can be taken together toform an optionally substituted heterocyclyl. In some embodiments, theoptionally substituted heterocyclyl can be an optionally substitutedtricyclic heterocyclyl, such as an optionally substituted,

wherein * each indicate a point of attachment to the 6-membered ring.

Formula (Id)

In some embodiments, L can be Formula (Id):

In some embodiments of Formula (Id), R^(1d) can be hydrogen. In otherembodiments of Formula (Id), R^(1d) can be an unsubstituted C₁₋₄ alkyl.

In some embodiments of Formula (Id), both R^(2d) and R^(2d1) can behydrogen. In other embodiments of Formula (Id), R^(2d) can be hydrogenand R^(2d1) can be an unsubstituted C₁₋₄ alkyl. In still otherembodiments of Formula (Id), R^(2d) can be hydrogen and R^(2d1) can be asubstituted C₁₋₄ alkyl. In yet still other embodiments of Formula (Id),R^(2d) can be hydrogen and R^(2d1) can be an optionally substitutedaryl(C₁₋₆ alkyl) or an optionally substituted heterocyclyl(C₁₋₆ alkyl).In some embodiments of Formula (Id), R^(2d) can be hydrogen and R^(2d1)can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In otherembodiments of Formula (Id), R^(2d) can be hydrogen and R^(2d1) can behydroxy. In still other embodiments of Formula (Id), R^(2d) and R^(2d1)both can be an optionally substituted C₁₋₄ alkyl.

In some embodiments of Formula (Id), m^(d) can be 0. In otherembodiments of Formula (Id), m^(d) can be 1.

In some embodiments of Formula (Id), ring B^(d) can be an optionallysubstituted C₅ cycloalkyl. In some embodiments, ring B^(d) can be anoptionally substituted

In some embodiments of Formula (Id), ring B^(d1) can be an optionallysubstituted pyridinyl having the structure

The C₅ cycloalkyl and/or pyridinyl ring can be unsubstituted orsubstituted with one or more substituents. Suitable substituentsinclude, but are not limited to, amino, mono-substituted amino,di-substituted amino, hydroxyalkyl, alkyl and alkoxy.

In some embodiments, A can be substituted. In other embodiments, A canbe unsubstituted. When A is substituted, possible substituent(s)includes those provided in the list of “substituted” along with thosedescribed herein.

In some embodiments, A can be an optionally substituted aryl. Forexample, A can be an optionally substituted phenyl. In some embodiments,A can be a para-substituted phenyl, a meta-substituted phenyl or anortho-substituted phenyl. In some embodiments, A can be a di-substitutedphenyl. For example, A can be a 3,4-substituted phenyl, such as

In some embodiments, A can be a substituted phenyl that is substitutedwith 3 more substituents. In other embodiments, A can be unsubstitutedphenyl. In some embodiments, A can be an optionally substitutednaphthyl.

In some embodiments and without limitation, A can be a phenylsubstituted with one or more substituents selected from an unsubstitutedC₁₋₄ alkyl, an optionally substituted C₁₋₄ alkyl, cycloalkyl, hydroxy,an optionally substituted C₁₋₄ alkoxy, C₁₋₄ alkoxy, halogen, haloalkyl,an optionally substituted haloalkoxy, nitro, amino, mono-substitutedamino, di-substituted amino, —O-amido, sulfenyl, alkyoxyalkyl, anoptionally substituted aryl (for example, an optionally substitutedphenyl), an optionally substituted monocyclic heteroaryl, an optionallysubstituted monocyclic heterocyclyl, an optionally substituted aryl(C₁₋₄alkyl), an optionally substituted monocyclic heteroaryl(C₁₋₄ alkyl), anoptionally substituted monocyclic heterocyclyl(C₁₋₄ alkyl), hydroxyalkyland aminoalkyl. In some embodiments, the optionally substituted C₁₋₄alkoxy can be further substituted, for example, further substituted witha substituent selected from C₁₋₄ alkyl, halo, hydroxy, C-carboxy,C-amido, amino, mono-alkyl amine, di-alkyl amine and an amino acid. Insome embodiments, the optionally substituted haloalkoxy can be furthersubstituted, for example, further substituted with an C₁₋₄ alkoxy. Insome embodiments, the optionally substituted heteroaryl can be furthersubstituted, for example, further substituted with an C₁₋₄ alkyl.

Examples of suitable substituents include, but are not limited to,methyl, ethyl, propyl (n-propyl and iso-propyl), butyl (n-butyl,iso-butyl and t-butyl), hydroxy, methoxy, ethoxy, propoxy (n-propoxy andiso-propoxy), butoxy (n-butoxy, iso-butoxy and t-butoxy), phenoxy,bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, cyano, N,N-di-methyl-amine, N,N-di-ethyl-amine,N-methyl-N-ethyl-amine, N-methyl-amino, N-ethyl-amino, amino, N-amido(for example, —NH—C(═O)C₁₋₄ alkyl), alkylthio (such as CH₃CH₃S—),N-sulfonamido (for example, —NH—S(O)₂C₁₋₄ alkyl), an optionallysubstituted phenyl, an optionally substituted imidazole, an optionallysubstituted morpholinyl, an optionally substituted pyrazole, anoptionally substituted pyrrolidinyl, an optionally substitutedpyridinyl, an optionally substituted piperidinyl, an optionallysubstituted piperidinone, an optionally substituted pyrrolidinone, anoptionally substituted pyrimidine, an optionally substituted pyrazine,an optionally substituted 1,2,4-oxadiazole, —(CH₂)₁₋₄—OH,—(CH₂)₁₋₂—NH(CH₃), an optionally substituted —(CH₂)₁₋₂-imidazole, anoptionally substituted —(CH₂)₁₋₂-pyrrolidinone, an optionallysubstituted —(CH₂)₁₋₂-imidazolidinone, —O(CH₂)₂—NH₂, —O(CH₂)₂—NH(CH₃),—O(CH₂)₂—N(CH₃)₂, —O—(CH₂)₂₋₄OH, —O(CH₂)₂OCH₃, an optionally substituted—O(CH₂)₀₋₂-cyclopentanone, an optionally substituted—O(CH₂)₀₋₂pyrrolidinone, an optionally substituted—O(CH₂)₀₋₂-morpholinyl, an optionally substituted —O(CH₂)₀₋₂-triazole,an optionally substituted —O(CH₂)₀₋₂-imidazole, an optionallysubstituted —O(CH₂)₀₋₂-pyrazole, an optionally substituted—O(CH₂)₀₋₂-tetrahydrofuran, an optionally substituted—O(CH₂)₀₋₂-pyrrolidinone, an optionally substituted—O(CH₂)₀₋₂-tetrazole, an optionally substituted —O(CH₂)₀₋₂-tetrazolone,

In some embodiments, A can be an optionally substituted cycloalkyl.Suitable examples of optionally substituted cycloalkyls include, but arenot limited to, an optionally substituted cyclohexyl and an optionallysubstituted cycloheptyl. In other embodiments, A can be an optionallysubstituted cycloalkenyl, for example, an optionally substitutedcyclohexenyl. In some embodiments, A can be an optionally substitutedbi-cyclic cycloalkenyl, such as

In some embodiments, A can be an optionally substituted aryl(C₁₋₂alkyl). In some embodiments, A can be an optionally substituted benzyl.

In some embodiments, A can be an optionally substituted mono-cyclicheteroaryl. In some embodiments, A can be an optionally substitutedmono-cyclic 5-membered heteroaryl. In other embodiments, A can be anoptionally substituted mono-cyclic 6-membered heteroaryl. In someembodiments, A can be an optionally substituted bi-cyclic heteroaryl.

In some embodiments, the optionally substituted heteroaryl can beselected from an optionally substituted imidazole, an optionallysubstituted thiazole, an optionally substituted furan, an optionallysubstituted thiophene, an optionally substituted pyrrole, an optionallysubstituted pyridine, an optionally substituted pyrimidine, anoptionally substituted pyrazine, an optionally substituted quinoline, anoptionally substituted imidazole, an optionally substituted oxazole, anoptionally substituted isoxazole, an optionally substitutedbenzoimidazole, an optionally substituted benzooxazole, an optionallysubstituted benzothiazole and an optionally substitutedimidazo[1,2-a]pyrimidine. In some embodiments, A can be an optionallysubstituted thiophene. In other embodiments, A can be an optionallysubstituted thiazole. In still other embodiments, A can be an optionallysubstituted pyridine. In yet still other embodiments, A can be anoptionally substituted pyrimidine. In some embodiments, A can be anoptionally substituted pyrazine. In other embodiments, A can be anoptionally substituted imidazole. In still other embodiments, A can bean optionally substituted benzoimidazole, an optionally substitutedbenzooxazole or an optionally substituted benzothiazole.

In some embodiments, A can be an optionally substituted heterocyclyl,for example, an optionally substituted mono-cyclic heterocyclyl or anoptionally substituted bi-cyclic heterocyclyl. In some embodiments, Acan be an optionally substituted

In other embodiments, A can be an optionally substituted

In still other embodiments, A can be an optionally substituted

In yet still other embodiments, A can be an optionally substituted

In some embodiments, A can be an optionally substituted

In other embodiments, A can be an optionally substituted

In still other embodiments, A can be an optionally substituted

In yet still other embodiments, A can be an optionally substituted

In some embodiments, A can be an optionally substituted

In some embodiments, A can be substituted with one or more R^(A)'s. Insome embodiments, one R^(A) can be present. In some embodiments, twoR^(A)'s can be present. In some embodiments, three R^(A)'s can bepresent. In some embodiments, four or more R^(A)'s can be present. Whentwo or more R^(A)'s are present, two or more R^(A)'s can be the same ortwo or more R^(A)'s can be different. In some embodiments, at least twoR^(A)'s can be the same. In some embodiments, at least two R^(A)'s canbe different. In some embodiments, all the R^(A)'s can be the same. Inother embodiments, all the R^(A)'s can be different. In someembodiments, A can have one of the following structures:

In some embodiments, R^(A) can be each independently selected from anunsubstituted C₁₋₄ alkyl, an optionally substituted C₁₋₄ alkyl,cycloalkyl, hydroxy, an optionally substituted C₁₋₄ alkoxy, C₁₋₄ alkoxy,halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino,mono-substituted amino, di-substituted amine, sulfenyl, alkyoxyalkyl,aryl, monocyclic heteroaryl, monocyclic heterocyclyl and aminoalkyl. Insome embodiments, the optionally substituted C₁₋₄ alkoxy can be furthersubstituted, for example, further substituted with a substituentselected from C₁₋₄ alkyl, halo, hydroxy, C-carboxy, C-amido, N-amido,amino, mono-alkyl amine, di-alkyl amine and an amino acid. In someembodiments, the optionally substituted haloalkoxy can be furthersubstituted, for example, further substituted with an C₁₋₄ alkoxy. Insome embodiments, the optionally substituted heteroaryl can be furthersubstituted, for example, further substituted with an C₁₋₄ alkyl.

In some embodiments, each R^(A) can be an alkyl, such as methyl, ethyl,propyl (n-propyl and iso-propyl) and/or butyl (n-butyl, iso-butyl andt-butyl).

In some embodiments, each R^(A) can be an optionally substituted alkoxy,for example, methoxy, ethoxy, propoxy (n-propoxy and iso-propoxy),butoxy (n-butoxy, iso-butoxy and t-butoxy), phenoxy, —O(CH₂)₂—NH₂,—O(CH₂)₂—NH(CH₃), —O(CH₂)₂—N(CH₃)₂, —O—(CH₂)₂₋₄OH,

—(CH₂)₂OCH₃, an optionally substituted —O(CH₂)₀₋₂-morpholinyl, anoptionally substituted —O(CH₂)₀₋₂-triazole, an optionally substituted—O(CH₂)₀₋₂-imidazole, an optionally substituted—O(CH₂)₀₋₂-cyclopentanone, an optionally substituted—O(CH₂)₀₋₂pyrrolidinone, an optionally substituted —O(CH₂)₀₋₂-pyrazole,an optionally substituted —O(CH₂)₀₋₂-tetrahydrofuran, an optionallysubstituted —O(CH₂)₀₋₂-pyrrolidinone, an optionally substituted—O(CH₂)₀₋₂-tetrazole, an optionally substituted —O(CH₂)₀₋₂-tetrazoloneand/or

In some embodiments, R^(A) can be substituted C₁₋₆ alkoxy substituted byone or more of the following: halo, hydroxy, C₁₋₄ alkyl, cyano, amino,mono-substituted amino, di-substituted amino, sulfonamidocarbonyl,hydroxamidine, C-amido, acyl, C-carboxy, O-carboxy, sulfonyl,S-sulfonamido, O-linked amino acid and carbonate ester.

In some embodiments, each R^(A) can be haloalkyl, for example,trifluoromethyl.

In some embodiments, each R^(A) can be an optionally substitutedhaloalkoxy, for example, difluoromethoxy, trifluoromethoxy,

In some embodiments, each R^(A) can be halogen, for example, chloro,bromo and/or fluoro.

In some embodiments, each R^(A) can be amino, a mono-substituted amineor a di-substituted amine. For examples, R^(A) can beN,N-di-methyl-amine, N,N-di-ethyl-amine, N-methyl-N-ethyl-amine,N-methyl-amino, N-ethyl-amino and/or amino.

In some embodiments, each R^(A) can be hydroxy.

In some embodiments, each R^(A) can be alkylthio, for example ethylthio.

In some embodiments, each R^(A) can be aminoalkyl, such as—(CH₂)₁₋₂—NH(CH₃).

In some embodiments, each R^(A) can be alkoxyalkyl, for example,—CH₂—O—CH₃.

In some embodiments, each R^(A) can be an optionally substitutedaryl(C₁₋₄ alkyl). In some embodiments, each R^(A) can be an optionallysubstituted monocyclic heteroaryl(C₁₋₄ alkyl). In some embodiments, eachR^(A) can be an optionally substituted monocyclic heterocyclyl(C₁₋₄alkyl). Non-limiting examples include an optionally substituted—(CH₂)₁₋₂-imidazole, an optionally substituted —(CH₂)₁₋₂-pyrrolidinone,an optionally substituted —(CH₂)₁₋₂-imidazolidinone.

In some embodiments, each R^(A) can be hydroxyalkyl, for example,—(CH₂)₁₋₄—OH.

In some embodiments, each R^(A) can be —O-amido, for example,

In some embodiments, each R^(A) can be —N-amido, for example,

In some embodiments, each R^(A) can be —N-sulfonamido, for example,

In some embodiments, each R^(A) can be aminoalkyl, for example, —CH₂—NH₂and/or —CH₂—N(CH₃)H.

In some embodiments, each R^(A) can be an optionally substituted aryl,for example, an optionally substituted phenyl.

In some embodiments, each R^(A) can be an optionally substitutedmono-cyclic heteroaryl, such as an optionally substituted imidazole, anoptionally substituted pyrazole, an optionally substituted pyridinyl, anoptionally substituted pyrimidine, an optionally substituted pyrazineand/or an optionally substituted 1,2,4-oxadiazole.

In some embodiments, each R^(A) can be an optionally substitutedmono-cyclic heterocyclyl, for example, an optionally substitutedpyrrolidinyl, an optionally substituted piperidinyl, an optionallysubstituted morpholinyl and/or an optionally substituted pyrrolidinone.

In some embodiments, Y can be an optionally substituted aryl. In someembodiments, Y can be a para-substituted phenyl, a meta-substitutedphenyl or an ortho-substituted phenyl. In some embodiments, Y can be amono-substituted phenyl, such as a mono-halo substituted phenyl. In someembodiments, Y can be a di-substituted phenyl, for example a di-halosubstituted phenyl. For example, mono-halo substituted phenyls anddi-halo substituted phenyls include, but are not limited to,

In some embodiments, Y can be di-substituted phenyl of the structure

In some embodiments, Y can be a substituted phenyl that is substitutedwith 3 more substituents. In other embodiments, Y can be unsubstitutedphenyl. In some embodiments, Y can be a substituted naphthyl. In otherembodiments, Y can be an unsubstituted naphthyl.

In some embodiments, Y can be an optionally substituted cycloalkyl(e.g., an optionally substituted cyclohexyl and an optionallysubstituted cycloheptyl). In other embodiments, Y can be an optionallysubstituted cycloalkenyl, for example, an optionally substitutedcyclohexenyl. In some embodiments, Y can be an optionally substitutedbi-cyclic cycloalkenyl, such as

In some embodiments, Y can be an optionally substituted mono-cyclicheteroaryl. In some embodiments, Y can be selected from an optionallysubstituted imidazole, an optionally substituted furan, an optionallysubstituted thiophene, an optionally substituted pyrrole, an optionallysubstituted pyrimidine, an optionally substituted pyrazine, anoptionally substituted pyridine, an optionally substituted pyrazole, anoptionally substituted oxazole and an optionally substituted isoxazole.In some embodiments, Y can be a substituted mono-cyclic heteroaryl,including those described herein. In some embodiments, Y can be anunsubstituted mono-cyclic heteroaryl, including those described herein.

In some embodiments, Y can be an optionally substituted bi-cyclicheteroaryl. In some embodiments, Y can be selected from an optionallysubstituted benzothiophene, an optionally substituted benzofuran, anoptionally substituted indole, an optionally substituted quinoline, anoptionally substituted isoquinoline, an optionally substitutedbenzooxazole, an optionally substituted benzoisoxazole, an optionallysubstituted benzoisothiazole, an optionally substituted benzothiazole,an optionally substituted benzoimidazole, an optionally substitutedbenzotriazole, an optionally substituted 1H-indazole and an optionallysubstituted 2H-indazole. In some embodiments, Y can be selected from anoptionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

In some embodiments, Y can be a substituted bi-cyclic heteroaryl,including those described herein. In some embodiments, Y can be anunsubstituted bi-cyclic heteroaryl, including those described herein.

In some embodiments, Y can be an optionally substituted heterocyclyl. Insome embodiments, Y can be an optionally substituted mono-cyclicheterocyclyl, such as an optionally substituted pyridinone. In otherembodiment, Y can be an optionally substituted bi-cyclic heterocyclyl.For example, Y can be an optionally substituted

an optionally substituted

or an optionally substituted

When Y is substituted, Y can be substituted with one or more R^(B)'s. Insome embodiments, each R^(B) can be independently selected from cyano,halogen, an optionally substituted C₁₋₄ alkyl, an unsubstituted C₂₋₄alkenyl, an unsubstituted C₂₋₄ alkynyl, an optionally substituted aryl,an optionally substituted 5 or 6 membered heteroaryl, an optionallysubstituted 5 or 6 membered heterocyclyl, hydroxy, C₁₋₄ alkoxy,alkoxyalkyl, C₁₋₄ haloalkyl, haloalkoxy, an unsubstituted acyl, anoptionally substituted —C-carboxy, an optionally substituted —C-amido,sulfonyl, carbonyl, amino, mono-substituted amine, di-substituted amineand

In some embodiments, when Y is an optionally substituted phenyl, thephenyl can be substituted 1, 2, 3 or more times with cyano, halogen, anoptionally substituted C₁₋₄ alkyl, an unsubstituted C₂₋₄ alkenyl, anunsubstituted C₂₋₄ alkynyl, an optionally substituted aryl, anoptionally substituted 5 or 6 membered heteroaryl, an optionallysubstituted 5 or 6 membered heterocyclyl, hydroxy, C₁₋₄ alkoxy, C₁₋₄haloalkyl (such as CF₃, CHF₂), haloalkoxy (such as OCF₃), anunsubstituted acyl, an optionally substituted —C-carboxy, an optionallysubstituted —C-amido, sulfonyl, amino, mono-C₁₋₄ alkyl amine, di-C₁₋₄alkyl amine and/or

In other embodiments, when Y is an optionally substituted mono-cyclicheteroaryl, the mono-cyclic heteroaryl can be substituted 1, 2, 3 ormore times with halo, an optionally substituted C₁₋₄ alkyl, anoptionally substituted phenyl and/or an unsubstituted acyl. In stillother embodiments, when Y is an optionally substituted bi-cyclicheteroaryl, the bi-cyclic heteroaryl can be substituted 1, 2, 3 or moretimes with halo, an optionally substituted C₁₋₄ alkyl, an optionallysubstituted phenyl, hydroxy, C₁₋₄ alkoxy, an unsubstituted acyl,carbonyl, cyano, amino, mono-C₁₋₄ alkyl amine and/or di-C₁₋₄ alkylamine.

In some embodiments, Y can be an optionally substituted benzothiophene.In some embodiments, Y can be a substituted benzothiophene. In otherembodiments, Y can be an unsubstituted benzothiophene. In someembodiments, the benzothiophene can be substituted with one or more ofthe following: halogen (such as fluoro, chloro and/or bromo), carbonyl,C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, NH₂ and/or mono-substituted amine. Forexample, the benzothiophene can be an optionally substituted

such as an optionally substituted

an optionally substituted

and an optionally substituted

In some embodiments, Y can be an optionally substituted benzofuran.

In some embodiments, Y can be an optionally substituted indole. In someembodiments, Y can be a substituted indole. In some embodiments, theindole can be substituted 1, 2, 3 or more time with phenyl (substitutedor unsubstituted), C₁₋₄ alkyl and/or halo. In other embodiments, Y canbe an unsubstituted indole.

In some embodiments, Y can be substituted with one or more halogen. Insome embodiments, Y can be substituted with one or more unsubstitutedC₁₋₄ alkyl. In some embodiments, Y can be substituted with more or morehydroxy. In some embodiments, Y can be substituted with one or moreoptionally substituted phenyl. In some embodiments, Y can be substitutedwith one or more alkoxy. In some embodiments, Y can be substituted withone or more acyl. In some embodiments, Y can be substituted with one ormore amino, mono-substituted amino, or di-substituted amino. In someembodiments, Y can be substituted with one or more haloalkyl. In someembodiments, Y can be substituted with one or more haloalkoxy. In someembodiments, Y can be substituted with one or more C-carboxy. In someembodiments, Y can be substituted with one or more C-amido. In someembodiments, Y can be substituted with one or more hydroxyalkyl.

In some embodiments, a compound of Formula (I) can be selected from thefollowing compounds: 1, 13-1, 100, 101, 102, 103, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116, 116a, 116b, 117, 117a, 117b,118, 118a, 118b, 119, 120, 120a, 120b, 121, 122, 122a, 122b, 123, 124,125, 126, 127, 128, 129, 131, 132, 133, 134, 138, 139, 142, 143, 144,145, 146, 147, 148, 151, 152, 153, 154, 155, 158, 159, 162, 163, 164,165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178,179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192,193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206,207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 218, 219, 221, 223,224, 225, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238,239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266,267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280,281, 282, 283, 284, 285, 286, 288, 289, 290, 291, 292, 293, 294, 295,296, 297, 298, 299, 300, 301, 306, 307, 308, 309, 310, 312, 313, 314,315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328,329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 342, 343,344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357,358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371,372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385,386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399,400, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414,415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442,443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456,457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486,487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498a, 498b, 498c,498d, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511,512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525,526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539,540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553,554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 567, 568,569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596,597, 598, 599, 600, 601, 602, 603, 604a, 604b, 604c, 604d, 605a, 605b,605c, 605d, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617,618, 619, 620, 621, 622, 623a, 623b, 624a, 624b, 625, 626, 627, 628,629, 630, 631, 632, 633a, 633b, 634, 635, 636, 637, 638, 639, 640, 641,642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655,656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669,670, 671, 672, 673, 674, 675, 676, 677, 678, 680, 681 and 682, or apharmaceutically acceptable salt of the foregoing. In some embodiments,a compound of Formula (I) can be selected from: 149, 150, 156, 157, 160,217, 220, 222, 229, 287, 302, 303, 304, 305, 311, 401, 473 and 474, or apharmaceutically acceptable salt of the foregoing. In some embodiments,a compound of Formula (I) can be selected from: 130, 135, 140 and 141,or a pharmaceutically acceptable salt of the foregoing. In someembodiments, a compound of Formula (I) can be 104 or 161, or apharmaceutically acceptable salt of the foregoing. In some embodiments,a compound of Formula (I) can be 136 or 137, or a pharmaceuticallyacceptable salt of the foregoing. In some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, cannot be acompound provided in PCT Publication WO 2014/031784, published Feb. 27,2014.

Pharmaceutical Compositions

Some embodiments described herein relate to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound nor cause appreciable damage or injury to an animal towhich delivery of the composition is intended.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks appreciable pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the pH and isotonicity of human blood.

As used herein, an “excipient” refers to an essentially inert substancethat is added to a pharmaceutical composition to provide, withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, pulmonary, topical,aerosol, injection and parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intranasal and intraocularinjections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection or implantation of the compounddirectly into the affected area, often in a depot or sustained releaseformulation. Furthermore, one may administer the compound in a targeteddrug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ. For example, intranasal or pulmonary deliveryto target a respiratory infection may be desirable.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Methods of Use

Some embodiments described herein relate to a method for ameliorating,treating and/or preventing a paramyxovirus viral infection, which cancomprise administering an effective amount of one or more compoundsdescribed herein, or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof).

Some embodiments described herein relate to a method for inhibitingviral replication of a paramyxovirus, which can comprise contacting acell infected with the virus with an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof).

Some embodiments described herein relate to a method for contacting acell infected with a paramyxovirus, which can comprise contacting a cellinfected with the virus with an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof).

In some embodiments, the paramyxovirus infection is a human respiratorysyncytial virus infection.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate arespiratory syncytial viral infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto prevent a respiratory syncytial viral infection. In some embodiments,an effective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to inhibit the replication a respiratory syncytialvirus. In some embodiments, an effective amount of one or more compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the RSV polymerasecomplex. In some embodiments, the RSV can be RSV A. In some embodiments,the RSV can be RSV B.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate ahendraviral infection and/or nipahviral infection. In some embodiments,an effective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to prevent a hendraviral infection and/ornipahviral infection. In some embodiments, an effective amount of one ormore compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit thereplication a hendravirus and/or nipahvirus. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to inhibit the hendravirus polymerase complexand/or nipahvirus polymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate ameasles. In some embodiments, an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to prevent a measles. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication ameasles virus. In some embodiments, an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the measles polymerasecomplex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate mumps.In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to prevent mumps. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication a mumpsvirus. In some embodiments, an effective amount of one or more compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the mumps polymerasecomplex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a sendaiviral infection. In some embodiments, an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to prevent a sendai viralinfection. In some embodiments, an effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,and/or a pharmaceutical composition that includes one or more compoundsdescribed herein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication a sendaivirus. In some embodiments, an effective amount of one or more compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the sendai viruspolymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a HPIV-1infection and/or HPIV-3 infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto prevent a HPIV-1 infection and/or HPIV-3 infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication of aHPIV-1 and/or HPIV-3. In some embodiments, an effective amount of one ormore compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit theHPIV-1 polymerase complex and/or HPIV-3 polymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a HPIV-2infection and/or HPIV-4 infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto prevent a HPIV-2 infection and/or HPIV-4 infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication of aHPIV-2 and/or HPIV-4. In some embodiments, an effective amount of one ormore compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit theHPIV-2 polymerase complex and/or HPIV-4 polymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a humanmetapneumoviral infection. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to prevent a humanmetapneumoviral infection. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit thereplication of a human metapneumovirus. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to inhibit the human metapneumovirus polymerasecomplex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate an upperrespiratory viral infection caused by a virus selected from ahenipavirus, a morbillivirus, a respirovirus, a rubulavirus, apneumovirus, and a metapneumovirus. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedtreat and/or ameliorate a lower respiratory viral infection caused by avirus selected from a henipavirus, a morbillivirus, a respirovirus, arubulavirus, a pneumovirus, and a metapneumovirus. In some embodiments,an effective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate one or more symptoms of aninfection caused by a virus selected from a henipavirus, amorbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and ametapneumovirus (such as those described herein).

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate an upperrespiratory viral infection caused by RSV infection, measles, mumps,parainfluenza infection, and/or metapneumovirus. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate a lower respiratory viralinfection caused by RSV infection, measles, mumps, parainfluenzainfection, and/or metapneumovirus. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedtreat and/or ameliorate one or more symptoms of an infection caused byRSV infection, measles, mumps, parainfluenza infection, and/ormetapneumovirus (such as those described herein).

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or amelioratebronchiolitis and/or tracheobronchitis due to a RSV infection and/orhuman parainfluenza virus 3 (HPIV-3) infection. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate pneumonia due to a RSVinfection and/or human parainfluenza virus 3 (HPIV-3) infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate croup dueto a RSV infection and/or human parainfluenza virus 1 (HPIV-1)infection.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate due tofever, cough, runny nose, red eyes, a generalized rash, pneumonia, anear infection and/or bronchitis due to measles. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate due to swelling of thesalivary glands, fever, loss of appetite and/or fatigue due to mumps.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to prevent a human parainfluenzaviral infection. In some embodiments, the human parainfluenza viralinfection can be a human parainfluenza virus 1 (HPIV-1). In otherembodiments, the human parainfluenza viral infection can be a humanparainfluenza virus 2 (HPIV-2). In other embodiments, the humanparainfluenza viral infection can be a human parainfluenza virus 3(HPIV-3). In other embodiments, the human parainfluenza viral infectioncan be a human parainfluenza virus 4 (HPIV-4). In some embodiments, oneor more compounds of Formula (I), or a pharmaceutically acceptable saltthereof, can be used to treat and/or ameliorate one or more subtypes ofhuman parainfluenza virus. For example, one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, can be used to treatHPIV-1 and/or HPIV-3.

The one or more compounds of Formula (I) or a pharmaceuticallyacceptable salt thereof, that can be used to treat, ameliorate and/orprevent a paramyxovirus viral infection can be a compound of Formula(I), or pharmaceutically acceptable salt thereof, provided in any of theembodiments described in the section under the “Compounds” headingabove.

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates such as fish, shellfish,reptiles and, in particular, mammals. “Mammal” includes, withoutlimitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats,cows, horses, primates, such as monkeys, chimpanzees, and apes, and, inparticular, humans. In some embodiments, the subject is human.

As used herein, the terms “prevent” and “preventing,” mean lowering theefficiency of viral replication and/or inhibiting viral replication to agreater degree in a subject who receives the compound compared to asubject who does not receive the compound. Examples of forms ofprevention include prophylactic administration to a subject who has beenor may be exposed to an infectious agent, such as a paramyxovirus (e.g.,RSV).

As used herein, the terms “treat,” “treating,” “treatment,”“therapeutic,” and “therapy” do not necessarily mean total cure orabolition of the disease or condition. Any alleviation of any undesiredsigns or symptoms of a disease or condition, to any extent can beconsidered treatment and/or therapy. Furthermore, treatment may includeacts that may worsen the subject's overall feeling of well-being orappearance, and may positively affect one or more symptoms or aspects ofthe disease while having effects on other aspects of the disease or onunrelated systems that may be considered undesireable.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, a therapeutically effective amount of compound can be theamount needed to prevent, treat, alleviate or ameliorate one or moresymptoms or conditions of disease or prolong the survival of the subjectbeing treated This response may occur in a tissue, system, animal orhuman and includes alleviation of the signs or symptoms of the diseasebeing treated. Determination of an effective amount is well within thecapability of those skilled in the art, in view of the disclosureprovided herein. The therapeutically effective amount of the compoundsdisclosed herein required as a dose will depend on the route ofadministration, the type of animal, including human, being treated, andthe physical characteristics of the specific animal under consideration.The dose can be tailored to achieve a desired effect, but will depend onsuch factors as weight, diet, concurrent medication and other factorswhich those skilled in the medical arts will recognize.

Various indicators for determining the effectiveness of a method fortreating a viral infection, such as a paramyxovirus, are known to thoseskilled in the art. Example of suitable indicators include, but are notlimited to, a reduction in viral load, a reduction in viral replication,a reduction in viral RNA, a reduction in time to seroconversion (virusundetectable in patient serum), a reduction of morbidity or mortality inclinical outcomes, and/or other indicator of disease response.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce viral titers to essentially undetectable or very lowlevels, for example, to less than 1.7 log₁₀ plaque forming unitsequivalents (PFUe)/mL, or less than 0.3 log₁₀ plaque forming unitsequivalents (PFUe)/mL. In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can reduce the viral loadcompared to the viral load before administration of the combination (forexample, 60 hours after receiving the initial dosage of thecombination). In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, described herein can reducethe viral load to lower than 1.7 log₁₀ (PFUe)/mL, or lower than 0.3log₁₀ (PFUe)/mL. In some embodiments, a combination of compoundsdescribed herein can achieve a reduction in viral titer in the serum ofthe subject in the range of about 1.5-log to about a 2.5-log reduction,about a 3-log to about a 4-log reduction, or a greater than about 5-logreduction compared to the viral load before administration of thecombination. For example, the viral load is measure beforeadministration of the combination, and several hours after receiving theinitial dosage of the combination (for example, 60 hours after receivingthe initial dosage of the combination).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15,20, 25, 50, 75, 100-fold or more reduction in the replication of aparamyxovirus relative to pre-treatment levels in a subject, asdetermined several hours after receiving the initial dosage of thecombination (for example, 60 hours after receiving the initial dosage ofthe combination). In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, described herein can result ina reduction of the replication of a paramyxovirus relative topre-treatment levels in the range of about 2 to about 5 fold, about 10to about 20 fold, about 15 to about 40 fold, or about 50 to about 100fold. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can result in a reduction of aparamyxovirus replication in the range of 1 to 1.5 log, 1.5 log to 2log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 logmore reduction of a paramyxovirus replication compared to the reductionof a paramyxovirus reduction achieved by ribavirin (Virazole®), or mayachieve the same reduction as that of ribavirin (Virazole®) therapy in ashorter period of time, for example, in one day, two days, three days,four days, or five days, as compared to the reduction achieved after 5days of ribavirin (Virazole®) therapy.

After a period of time, infectious agents can develop resistance to oneor more therapeutic agents. The term “resistance” as used herein refersto a viral strain displaying a delayed, lessened and/or null response toa therapeutic agent(s). For example, after treatment with an antiviralagent, the viral load of a subject infected with a resistant virus maybe reduced to a lesser degree compared to the amount in viral loadreduction exhibited by a subject infected with a non-resistant strain.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a subject infected withRSV that is resistant to one or more different anti-RSV agents (forexample, ribavirin). In some embodiments, development of resistant RSVstrains is delayed when subjects are treated with a compound of Formula(I), or a pharmaceutically acceptable salt thereof, compared to thedevelopment of RSV strains resistant to other RSV drugs.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can decrease the percentage of subjects thatexperience complications from a RSV viral infection compared to thepercentage of subjects that experience complication being treated withribavirin. For example, the percentage of subjects being treated with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,that experience complications can be 10%, 25%, 40%, 50%, 60%, 70%, 80%and 90% less compared to subjects being treated with ribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound described herein, can be used in combination with one or moreadditional agent(s). In some embodiments, a compound of Formula (I), ora pharmaceutically acceptable salt thereof, can be used in combinationwith one or more agents currently used in a conventional standard ofcare for treating RSV. For example, the additional agent can beribavirin, palivizumab, and RSV-IGIV. For the treatment of RSV,additional anti-RSV agents include but are not limited to an anti-RSVantibody, a fusion protein inhibitor, an N-protein inhibitor, a RSVpolymerase inhibitor, an IMPDH inhibitor, an interferon and an othercompound that inhibits the RSV virus, or a pharmaceutically acceptablesalt of any of the foregoing. A non-limiting list of examples ofadditional agents is provided herein.

anti-RSV RSV-IGIV (RespiGam ®) antibodiespalivizumab (Synagis ®, a chimeric humanized IgG monoclonal antibody)motavizumab (MEDI-524, humanized monoclonal antibody) fusion protein1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2- inhibitorsyl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771)4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic-acid (RFI-641)4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonic acid,disodium salt (CL387626)2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068)2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol (TMC-353121)5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol (VP-14637, MDT-637)N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13)2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591)1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (C15)(R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[1′,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981)[2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300) BTA-C286N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-l-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806)an anti-RSV nanobody (e.g., ALX-0171 (a trivalent nanobody, Ablynx)a peptide fusion inhibitor (such as a peptide having the sequenceDEFDASISQVNEKINQSLAFIRKSDELL (T-67) a peptide having the sequenceFDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-118) N-protein(S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H- inhibitorsbenzo[e][1,4]diazepin-3-yl)urea (RSV-604)STP-92 (siRNA delivered through nanoparticle based deliverysystems, Sirnaomics) iKT-041 (Inhibikase) RSV polymerase6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-inhibitorsdihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403)N-cyclopropyl-5-(4-(2-(pyrrolidin-l-yl)benzamido)benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione (CASReg. No. 851658-10-1) AZ27 IMPDH ribavirin inhibitors5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide(EICAR)4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin)1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Taribavirin, viramidine)1,3,4-thiadiazol-2-ylcyanamide (LY253963)tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497)(4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid)2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil)Interferons Type 1 interferon Type 2 interferon Type 3 interferonan alpha-interferon (IFN-α) Pegylated interferon-alpha-2a (PEGASYS ®)Pegylated interferon-alpha-2b (PEG-INTRON ®)interferon alfacon-1 (INFERGEN ®) beta-interferon (IFN-β)lambda-interferon (IFN-λ) other compoundsa double stranded RNA oligonucleotide5-methyl-N-[4-(trifluoromethyl)phenyl]-isoxazole-4-carboxamide(leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003)an intratracheal formulation of recombinant human CC10 (CG-100)high titer, human immunoglobulin (RI-001, ADMA Biologics Inc.)a non-neutralizing mAb against the G protein (mAb 131-2G)ALN-RSV01 (an siRNA agent with the sense strand sequence (5′ to3′) GGCUCUUAGCAAAGUCAAGdTdT (SEQ ID NO. 3) and theantisense strand sequence (5′ to 3′)CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 4) ALN-RSV02 Medi-559 Medi-534Medi-557 ALN-RSV01 and/or ALN-RSV02 can be found in U.S. Publication No.2009/0238772, filed Dec. 15, 2008 (Alnylam Pharmaceuticals). ALX-0171described in U.S. Publication No. 2012/0128669, filed Jun. 7, 2010.T-67, SEQ ID NO: 1, U.S. Pat. No. 6,623,741, filed Feb. 29, 2000. T-118,SEQ ID NO: 2, U.S. Pat. No. 6,623,741, filed Feb. 29, 2000.

Other examples of compounds that can be used in combination with acompound of Formula (I), or a pharmaceutically acceptable salt, includethose provided in WO 2013/186333, published Dec. 19, 2013; WO2013/186332, published Dec. 19, 2013; WO 2013/186335, published Dec. 19,2013; WO 2013/186334, published Dec. 19, 2013; WO 2012/080447, publishedJun. 21, 2012; WO 2012/080449, published Jun. 21, 2012; WO 2012/080450,published Jun. 21, 2012; WO 2012/080451, published Jun. 21, 2012; WO2012/080446, published Jun. 21, 2012; WO 2010/103306, published Sep. 16,2010; WO 2012/068622, published May 31, 2012; WO 2005/042530, publishedMay 12, 2005; WO 2006/136561, published Dec. 28, 2006; WO 2005/058869,published Jun. 30, 2005; U.S. 2013/0090328, published Apr. 11, 2013; WO2014/009302, published Jan. 16, 2014; WO 2011/005842, published Jan. 13,2011; U.S. 2013/0273037, published Oct. 17, 2013; U.S. 2013/0164280,published Jun. 27, 2013; U.S. 2014/0072554, published Mar. 13, 2014; WO2014/031784, published Feb. 27, 2014 and WO 2014/031784, published Feb.27, 2014, all of which are hereby incorporated by reference.

In combination therapy, the additional agents can be administered inamounts that have been shown to be effective for those additionalagents. Such amounts are known in the art; alternatively, they can bederived from viral load or replication studies using the parameters for“effective amount” set forth above. Alternatively, the amount used canbe less than the effective monotherapy amount for such additionalagents. For example, the amount used could be between 90% and 5% of suchamount, e.g., 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%, orintermediate values between those points.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered with one or more additionalagent(s) together in a single pharmaceutical composition. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered with one or more additional agent(s)as two or more separate pharmaceutical compositions. For example, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be administered in one pharmaceutical composition, and at least oneof the additional agents can be administered in a second pharmaceuticalcomposition. If there are at least two additional agents, one or more ofthe additional agents can be in a first pharmaceutical composition thatincludes a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one of the other additional agent(s) can bein a second pharmaceutical composition.

The order of administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, with one or more additionalagent(s) can vary. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered prior toall additional agents. In other embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered priorto at least one additional agent. In still other embodiments, a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, can beadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered subsequentto the administration of at least one additional agent. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered subsequent to the administration ofall additional agents.

A potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described above (including the table),including pharmaceutically acceptable salts and prodrugs thereof, may bea reduction in the required amount(s) of one or more compounds describedabove (including the table) (including pharmaceutically acceptable saltsand prodrugs thereof) that is effective in treating a disease conditiondisclosed herein (for example, RSV), as compared to the amount requiredto achieve same therapeutic result when one or more compounds describedabove (including the table), including pharmaceutically acceptable saltsthereof, are administered without a compound of Formula (I), or apharmaceutically acceptable salt thereof. For example, the amount of acompound described above (including the table), including apharmaceutically acceptable salt and prodrug thereof, can be lesscompared to the amount of the compound described above (including thetable), including a pharmaceutically acceptable salt and prodrugthereof, needed to achieve the same viral load reduction whenadministered as a monotherapy. Another potential advantage of utilizinga compound of Formula (I), or a pharmaceutically acceptable saltthereof, in combination with one or more additional agent(s) describedabove (including the table), including pharmaceutically acceptable saltsand prodrugs thereof, is that the use of two or more compounds havingdifferent mechanism of actions can create a higher barrier to thedevelopment of resistant viral strains compared to the barrier when acompound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described above (including the table),including pharmaceutically acceptable salts and prodrugs thereof, mayinclude little to no cross resistance between a compound of Formula (I),or a pharmaceutically acceptable salt thereof, and one or moreadditional agent(s) described above (including the table) (includingpharmaceutically acceptable salts and prodrugs thereof); differentroutes for elimination of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described above (including the table) (includingpharmaceutically acceptable salts and prodrugs thereof); little to nooverlapping toxicities between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described above (including the table) (includingpharmaceutically acceptable salts and prodrugs thereof); little to nosignificant effects on cytochrome P450; and/or little to nopharmacokinetic interactions between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described above (including the table), includingpharmaceutically acceptable salts and prodrugs thereof).

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.The dosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

Synthesis

Compounds of Formula (I), and those described herein may be prepared invarious ways. Some compounds of Formula (I) can be obtained commerciallyand/or prepared utilizing known synthetic procedures. General syntheticroutes to the compounds of Formula (I), and some examples of startingmaterials used to synthesize the compounds of Formula (I) are shown anddescribed herein. The routes shown and described herein are illustrativeonly and are not intended, nor are they to be construed, to limit thescope of the claims in any manner whatsoever. Those skilled in the artwill be able to recognize modifications of the disclosed syntheses andto devise alternate routes based on the disclosures herein; all suchmodifications and alternate routes are within the scope of the claims.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1

To a mixture of 1-1 (3.65 g, 20 mmol) in NMP:THF (2 mL/20 mL), Fe(acac)₃(622 mg, 2 mmol) was added. The solution was cooled to 0° C. andi-PrMgCl (20 mL, 2N) was added slowly at 0° C. The solution was stirredfor 2 h at 0° C. The solution was extracted with EA, and washed withbrine. The organic phase was concentrated to give crude 1-2 as acolorless solid (2.4 g, 63.5%). +ESI-MS: m/z 190.1 [M+H]⁺.

To a mixture of 1-2 (1 g, 5.29 mmol) and 1-3 (1.03 g, 5.29 mmol) in DMF(30 mL) were added Pd(dppf)Cl₂ (420 mg, 0.529 mmol) and a freshlyprepared KF solution (2.57 g in 10 mL of water). The system was degassedand then charged with nitrogen 3 times. The mixture was stirred undernitrogen at 70° C. using an oil bath for 8 h. The reaction solution wascooled to r.t., diluted with EA and separated from the water layer. TheEA solution was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified on a silica gel column to give 1-4 as acolorless solid (0.5 g, 31%). +ESI-MS: m/z 306.0 [M+H]⁺.

To a mixture of 1-4 (900 mg, 2.95 mmol), 1-5 (1.07 g, 2.95 mmol) and KF(0.684 g, 11.8 mmol) in DMF (10 mL) was added Pd(dppf)Cl₂ (228 mg, 0.295mmol). The system was degassed and then charged with nitrogen 3 times.The mixture was stirred under nitrogen at 70° C. using an oil bath for 8h. The reaction solution was cooled to r.t., diluted with EA and H₂O.The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated to give crude 1-6 (1 g). +ESI-MS: m/z 342.1 [M+H]⁺.

A mixture of 1-6 (1 g, 2.9 mmol) and NBS (516 mg, 2.9 mmol) in a mixtureof THF (10 mL) and H₂O (1 mL) was stirred at r.t. for 30 mins. Thesolution was diluted with water and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with a sat. Na₂S₂O₃solution, followed by brine. The solution was dried over Na₂SO₄ andevaporated to give crude 1-7 (1 g). +ESI-MS: m/z 392.0 [M+H]⁺.

To a solution of 1-7 (1 g, 2.55 mmol) in a mixture of THF (5 mL) andMeOH (0.5 mL) was added NaBH₄ (193 mg, 5.1 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 mins with TLC monitoring. The reaction wasquenched by the addition of H₂O and extracted with EA. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified on a silica gel column to give1-8 (200 mg, 20%). +ESI-MS: m/z 394.0 [M+H]⁺.

A mixture of 1-8 (200 mg, 0.50 mmol) and sat. NH₄OH/EtOH (1 mL/5 mL) ina sealed tube was heated to 70° C. for 6 h. The solution was removedunder reduced pressure to give crude 1-9 (160 mg, 90.0%), which was usedfor next step directly without purification. +ESI-MS: m/z 331.1 [M+H]⁺.

To a solution of 1-9 (65 mg, 0.363 mmol), HATU (172 mg, 0.45 mmol) andDIPEA (117 mg, 0.909 mmol) in anhydrous DMF (1 mL) was added 1-10 (100mg 0.303 mmol) at 25° C. The solution was stirred for 10 h at r.t. Thesolution was diluted with 1.0 N aqueous NaHCO₃ solution (2×40 mL) andextracted with EA (2×20 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue was purified on a silica gel column to give 1 (100mg, 67.1%). +ESI-MS: m/z 495.1 [M+H]⁺.

Example 2 Preparation of Compound 100

A solution of 2,4,6-trichloropyridine (6.5 g, 36 mmol) in anhydrousmethanol (20 mL) was added MeONa (2.9 g, 54 mmol) at 0° C. The reactionmixture was stirred at r.t. for 12 h. The reaction was quenched with dryice, and the mixture was filtered. The solution was concentrated underreduced pressure, and the residue was dissolved in EA. The mixture waswashed with water, and the organic layers were dried over NaSO₄. Thesolvent was concentrated to give 1-12 (4.2 g, 67%).

Compound 100 was prepared using 1-12 and4-(cyclopropylmethoxy)-3-methoxybenzoic acid, and by following asynthetic route, which closely follows that described for thepreparation of 1. 100: +ESI-MS: m/z 483.1 [M+H]+.

Example 3 Preparation of Compound 101

To a solution of 2-1 (3 g, 14 mmol) and the boronic acid (2.5 g, 14mmol) in dioxane/H₂O (30 mL/5 mL) was added Pd(dppf)Cl₂ (1.02 g, 1.4mmol) and Cs₂CO₃ (6.8 g, 21 mmol). The system was degassed and thencharged with nitrogen for 3 times. The mixture was stirred undernitrogen at 80° C. in an oil bath for 2 h. The solution was cooled tor.t., diluted with EA and separated from the water layer. The EAsolution was washed by brine, dried over Na₂SO₄ and concentrated. Theresidue was purified on a silica gel column to give 2-2 (2 g, 47.9%).

To a solution of 2-2 (2 g, 6.7 mmol) in MeOH/DCM (20 mL/20 mL) was addedNaBH₄ (510 mg, 13.4 mmol) slowly at 0° C. The solution was stirred for10 mins and heated to 50° C. and stirred for 2 h. The solution wasquenched with H₂O and extracted with EA. The solution was concentratedto give crude 2-3 (1.81 g, 100%).

To a solution of 2-3 (1.81 g, 6.7 mmol) in DMF was added imidazole (1.36g, 1.34 mmol) at r.t. TBSCl (201 mg, 1.34 mmol) was added. The solutionwas stirred for 18 h. The solution was washed with water and extractedwith EA. The organic phase was concentrated to give 2-4 (1.8 g, 70.0%).ESI-LCMS: m/z 385.9 [M+H]⁺.

Compound 2-10 was prepared using 2-4 and4-(cyclopropylmethoxy)-3-methoxybenzoic acid, and by following asynthetic route, which closely follows that described for thepreparation of 1. ¹H-NMR (400 MHz, CDCl₃), δ=8.00 (d, J=5.51 Hz, 1H)7.87 (br. s., 1H) 7.78 (s, 1H) 7.81 (s, 1H) 7.34 (s, 1H) 7.26 (d, J=8.38Hz, 1H) 7.14 (t, J=8.71 Hz, 1H) 6.92 (br, 1H) 6.74 (d, J=8.38 Hz, 1H)5.13 (d, J=4.41 Hz, 2H) 4.72 (s, 2H) 3.71-3.85 (m, 5H) 1.09 (br, 1H),0.83 (s, 10H) 0.46-0.56 (m, 2H), 0.19-0.30 (m, 2H), 0.00 (s, 7H).

To a solution of 2-10 (100 mg, 0.163 mmol) in dioxane (2 mL) was addedconcentrated HCl (2 mL) at r.t. and the mixture was stirred for 30 mins.The solution was quenched by aqueous NaHCO₃ solution and extracted byEA. The combined organic layers were washed by brine, dried over Na₂SO₄and concentrated. The residue was purified by prep-HPLC(FA) to give 2-11(30 mg, 37.0%) as a white solid. +ESI-MS: m/z 498.9 [M+H]⁺.

The solution of 2-11 (100 mg, 0.20 mmol) in THF (2 mL) was added MeMgBr(1 mL, 3 mmol) at r.t. and the mixture was stirred for 2 h. The solutionwas quenched with H₂O and extracted with EA. The combined organic layerswere washed by brine, dried over Na₂SO₄ and concentrated. The residuewas purified by prep-TLC (PE:EA=1:1) to give 101 (20 mg, 19.4%) as awhite solid. +ESI-MS: m/z 514.9 [M+H]⁺.

Example 4 Preparation of Compound 102

To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was addedNBS (14 g, 80 mmol). The mixture was stirred for 1 h. The solvent wereremoved under reduced pressure. Purification by column chromatography onsilica gel (PE:EA=2:1) provided 3-2 as white solid (9.6 g, 99%).+ESI-MS: m/z 239.0 [M+H]+

To a solution of 3-2 (9.6 g, 40 mmol) and K₂CO₃ (5.4 g, 40 mmol) in DMF(50 mL) at 40° C. was added CH₃I (6 g, 40 mmol). The mixture was stirredfor 2 h at r.t. The solution was poured into water and extracted withEtOAc. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE:EA=20:1) to provide 3-3 (3 g, 30%).+ESI-MS: m/z 253.0 [M+H]+.

Compound 102 was obtained by closely following the procedure forobtaining 1 using 3-3 and 3,4-dimethoxybenzoic acid. Compound 102 wasobtained as a white solid. +ESI-MS: m/z 470.1 [M+H]⁺.

Example 5 Preparation of Compound 103

To a stirring mixture of 2,6-dichloropyridine (270 mg, 1.82 mmol) and7-fluoro-1H-benzo[d]imidazole (248 mg, 1.82 mmol) in DMF (3 mL) wasadded Cs₂CO₃ (709 mg, 2.2 mmol). The mixture was reacted at 120° C. for2 h and then cooled to r.t. The mixture was diluted with EtOAc andwashed with a sat. NaCl solution. The layers were separated. The aqueouslayer was extracted with EtOAc (2×25 mL). The combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. Chromatography of the residue afforded 4-1 (300 mg) as a whitesolid. LCMS: m/z 248.1 [M+H]⁺.

Compound 103 was obtained as a yellow oil (100 mg) by closely followingthe procedure for obtaining 1 using 4-1 and 3,4-dimethoxybenzoic acid.LCMS: m/z 437.25 [M+H]⁺.

Example 6 Preparation of Compound 104

To a solution of 5-1 (10 g, 44.0 mmol) in DMF (150 mL) was added NaH(7.0 g, 0.177 mol), and the mixture was stirred at 0° C. for 30 mins.The solution was treated with PMBCl (11.67 g, 0.0748 mol), and stirredat r.t. overnight. After complete conversion, the reaction was quenchedwith MeOH and H₂O, and extracted with EA. The organic phase wasconcentrated to give 5-2 (11 g, 87.2%). +ESI-MS: m/z 375.9 [M+H]⁺.

To a solution of 5-2 (36 g, 96 mmol) in toluene (400 mL) was added(CH₃)₆Sn₂ (47.0 g, 144.0 mmol). The mixture was bubbled with nitrogengas and stirred at 100° C. for 3 h. The mixture was concentrated invacuum to give the crude product, which was purified by columnchromatography to give 5-3 (22 g). +ESI-MS: m/z 414.0 [M+H]⁺.

To a solution of 5-8 (30 g, 134 mmol) in anhydrous THF (500 mL) wasadded LiAlH₄ (7.6 g, 200 mmol) in portions at 0° C., and the mixture wasstirred at r.t. for 2 h (monitored by TLC). The reaction was quenchedwith a sat. NH₄Cl solution, and extracted with EA to give the crudeproduct, which was purified by column chromatography to give 5-9 (22 g).+ESI-MS: m/z 183.0 [M+H]⁺.

To a solution of 5-9 (22 g, 121 mmol) in THF (400 mL) was added NBS(25.7 g, 145 mmol), and the mixture was stirred at r.t. overnight(monitored by TLC). The reaction was quenched with a sat. Na₂S₂O₃solution, and extracted with EA to give the crude product, which waspurified by column chromatography to give 5-10 (23 g). +ESI-MS: m/z460.9 [M+H]⁺.

To a solution of 5-10 (22 g, 84.6 mmol) in anhydrous THF (200 mL) wasadded NaH (8.12 g, 33.85 mmol) in portions at 0° C., and the mixture wasstirred at 0° C. for 30 mins. MOMCl (27.08 g, 338.5 mmol) was added, andthe mixture was stirred at r.t. for 4 h. The reaction was quenched withwater and extracted with EA. The organic layer was dried over sodiumsulfate, and concentrated in vacuum to give the crude product, which waspurified by column chromatography to give 5-4 (21 g). +ESI-MS: m/z 304.9[M+H]⁺.

To a solution of 5-3 (6.36 g, 15.4 mmol) in DMF (50 mL) were added 5-4(4.7 g, 15.4 mmol), KF (3.7 g, 61.6 mmol) and Pd(PPh₃)₂Cl₂ (324 mg, 0.46mmol). The mixture was bubbled with nitrogen gas and stirred at 100° C.overnight. The mixture was diluted with water and extracted with EA. Theorganic layer was dried over sodium sulfate, and concentrated in vacuumto give the crude product, which was purified by column chromatographyto give 5-5 (3.8 g). +ESI-MS: m/z 474.1 [M+H]⁺.

To a solution of 5-5 (4.5 g, 9.51 mmol) in THF (30 mL) was added 10% HCl(30 mL), and stirred 110° C. overnight. The mixture was cooled to r.t.,and the pH was adjusted to 7.0 by adding a sat. NaHCO₃ solution. Themixture was extracted with EA. The organic layer was dried over sodiumsulfate, and concentrated in vacuum to give 5-6 (2.0 g), which was usedin the next step without purification. +ESI-MS: m/z 310.0 [M+H]⁺.

To a solution of 5-6 (1.3 g, 4.2 mmol) in THF (100 mL) was added PPh₃(1.32 g, 5.05 mmol), and the mixture was stirred at r.t. for 10 mins.DIAD (1.01 g, 5.05 mmol) was added in portions, and the mixture stirredat refluxed for 4 h. The mixture was concentrated in vacuum to give thecrude product, which was purified by column chromatography to give 5-7(0.7 g). +ESI-MS: m/z 292.0 [M+H]⁺.

Compound 104 was obtained as a white solid (50 mg) by closely followingthe procedure for obtaining 1 by using 5-7 and 3,4-dimethoxybenzoicacid. +ESI-MS: m/z 481.1 [M+H]⁺.

Example 7 Preparation of Compound 105

To a solution of 6-1 (196 mg, 1.0 mmol), 1,4-dibromobutane-2,3-dione(241 mg, 1.0 mmol) in DCM (3 mL) was added AgOTf (255 mg, 1.0 mmol). Thereaction was carried out at 80° C. under microwave irradiation for 15mins. The mixture was concentrated at low pressure. The residue waspurified by silica gel column (PE/EA) to 6-2 (270 mg, 80%). +ESI-MS: m/z339.9 [M+H]⁺.

Compound 105 was obtained (100 mg, 48%) by closely following theprocedure for obtaining 1 using 6-2 and 3,4-dimethoxybenzoic acid.+ESI-MS: m/z 442.9 [M+H]⁺.

Compound 106 was prepared using 2,6-dibromopyridine,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid, and by closely following a syntheticroute, which closely follows that described for the preparation of 1.+ESI-MS: m/z 452.9 [M+H]⁺.

Compound 107 was prepared using 3,4-dimethoxybenzoic acid and3-bromo-5-(7-fluorobenzo[b]thiophen-3-yl)-1-propyl-1H-1,2,4-triazole,and by closely following a synthetic route, which closely follows thatdescribed for the preparation of 1. +ESI-MS: m/z 485.0 [M+H]⁺.

Compound 108 was prepared using 2,4-dibromothiazole,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid, and by closely following a syntheticroute, which closely follows that described for the preparation of 1.+ESI-LCMS: m/z 459.0 [M+H]+.

Compound 109 was prepared using 2,4-dichloro-5-methoxypyrimidine,(3-chloro-4-fluorophenyl) boronic acid and4-(2-hydroxyethoxy)-3-methoxybenzoic acid, and by closely following asynthetic route, which closely follows that described for preparationof 1. +ESI-MS: m/z 506.1 [M+H]⁺.

Compound 110 was prepared using 2-hydroxy-4,5-dimethoxybenzoic acid and2-amino-1-(6-(7-fluorobenzo[b]thiophen-3-yl)-4-methoxypyridin-2-yl)ethanol, and by following a synthetic route, which closely follows thatdescribed for preparation of 1. Compound 110 was obtained as a whitesolid. +ESI-MS: m/z 498.9[M+H]⁺.

Compound 111 was obtained by closely following the procedure forobtaining 1 by using 2,4-dibromothiazole,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid. Compound 111 was obtained as a whitesolid. +ESI-LCMS: m/z 466.9 [M+H]⁺.

Compound 112 was prepared using 4-chloro-2-iodo-6-methoxypyrimidine,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid, and by following a synthetic route, whichclosely follows that described for preparation of 1. +ESI-MS: m/z 484.1[M+H]⁺.

Example 8 Preparation of Compound 113

To a solution of 7-1 (7.5 g, 27.17 mmol) in THF (100 mL) was addedslowly i-PrMgCl (25 mL, 2M in THF) at r.t., and the mixture stirred for10 mins. The solution was quenched with MeOH and diluted with DCM (20mL). The solution was washed by brine, dried over Na₂SO₄ andconcentrated to give crude 7-2 (5 g, 94.3%).

To a solution of 7-2 (1 g, 5.1 mmol), the tin reagent (3.71 g, 10.2mmol) and KF (1.18 g, 20.4 mmol) in DMF (10 mL) was added Pd(dppf)Cl₂(372 mg, 0.51 mmol). The system was degassed and then charged withnitrogen for 3 times. The mixture was stirred under nitrogen at 80° C.in an oil bath for 15 h. The solution was cooled to r.t. The mixture wasdiluted with EA. The EA solution was washed by brine, dried over Na₂SO₄and concentrated to give crude 7-3 (360 mg, 44.2%).

To a solution of 7-3 (360 mg, 2.25 mmol) in DCM (5 mL) was added NBS(480 mg, 2.7 mmol). The mixture was stirred at r.t. for 30 mins with TLCmonitoring. The solution was quenched by aqueous Na₂S₂O₃ solution andextracted by EA. The combined organic layers were dried over Na₂SO₄ andconcentrated. The residue was purified by prep-HPLC(FA) to give 7-4 (250mg, 46.2%).

To a solution of 7-4 (480 mg, 2 mmol) and the dioxaborolane reagent (558mg, 2 mmol) in dioxane/H₂O (10 mL/2 mL) were added Pd(dppf)Cl₂ (146 mg,0.2 mmol) and Cs₂C03 (975 mg, 3 mmol). The system was degassed and thencharged with nitrogen for 3 times. The mixture was stirred undernitrogen at 80° C. in an oil bath for 15 h. The solution was cooled tor.t., diluted with EA and separated from the water layer. The EAsolution was washed by brine, dried over Na₂SO₄ and concentrated. Theresidue was purified on a silica gel column to give 7-5 (400 mg, 64.5%).

To a solution of 7-5 (550 mg, 1.77 mmol) in DCM (5 mL) was added DIPEA(685 mg, 5.31 mmol) and TMSOTf (589 mg, 2.65 mmol) at 0° C. The solutionwas stirred for 2 h at r.t. The solution was concentrated and theresidue was dissolved in THF (10 mL) and FLO (1 mL). NBS (471 mg, 2.65mmol) was added at r.t., and stirred for 1.5 h. The solution wasevaporated at low pressure. The residue was purified by chromatography(PE:EA=3:1) to give 7-6 (600 mg, 86.9%).

Compound 113 was prepared from 7-6 and 3,4-dimethoxybenzoic acid byfollowing a synthetic route, which closely follows that described forthe preparation of 1. Compound 113 was obtained as white solids.+ESI-MS: m/z 492.0 [M+H]⁺.

To a solution of 8-1 (90 mg, 0.19 mmol) in THF (5 mL) was added CH₃MgBr(3 M, 0.64 M) at 0° C., and stirred at r.t. overnight. The reaction wasquenched with NH₄Cl solution and extracted with EA. The organic layerwas dried over sodium sulfate, then concentrated in vacuum to give thecrude product, which was purified by prep-HPLC to give 114 (18 mg) as awhite solid. +ESI-MS: m/z 498.1 [M+H]⁺.

Compound 115 (57 mg, 60%) was obtained by closely following theprocedure for obtaining 114 by using 9-1 (120 mg, 0.2 mmol). Compound115 was obtained as a white solid. +ESI-MS: m/z 494.9 [M+H]⁺.

Compound 116 was obtained by closely following the procedures forobtaining 100 and 114 using7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indoleand 4-ethoxy-3-methoxybenzoic acid. Compound 116 was obtained as a whitesolid. +ESI-MS: m/z 494.2 [M+H]⁺.

Individual enantiomers of 116 (116a and 116b) were obtained by SFCseparation of a racemic mixture of 116. +ESI-MS: m/z 494.2 [M+H]⁺.

Compound 117 was obtained by closely following the procedures forobtaining 100 and 114 using7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indoleand 4-(2-hydroxyethoxy)-3-methoxybenzoic acid. Compound 117 was obtainedas a white solid. +ESI-MS: m/z 510.2 [M+H]⁺.

Individual enantiomers of 117 (117a and 117b) were obtained by SFCseparation of a racemic mixture of 117. +ESI-MS: m/z 510.1 [M+H]⁺.

Compound 118 was prepared using1-amino-2-(6-(3-bromo-4-fluorophenyl)-5-methoxypyridin-2-yl)propan-2-oland 4-(2-fluoroethoxy)-3-methoxybenzoic acid and4-(2-fluoroethoxy)-3-methoxybenzoic acid, and by following a syntheticroute, which closely follows that described for preparation of 100 and114. +ESI-MS: m/z 551.9 [M+H]⁺.

Individual enantiomers of 118 (118a and 118b) were obtained by SFCseparation of a racemic mixture of 118. +ESI-MS: m/z 551.9 [M+H]⁺.

To a stirring mixture ofN-(2-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3-methoxybenzamide(50 mg, 0.1 mmol) in THF at r.t. under argon was added a solution ofMeMgCl in THF (0.5 mL, 1.0 mmol). The mixture was reacted at r.t. for 2h. The mixture was diluted with EtOAc and slowly quenched with a sat.NH₄Cl solution. The mixture was stirred at r.t. for 10 mins and then thelayers were separated. The aqueous layer was extracted with EtOAc. Theorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude mixture was purified via silica gel columnand further purified via prep-HPLC to afford 119 as a white solid. LCMS:m/z 507.1 [M+H]⁺.

Compound 120 was prepared usingN-(2-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-4-(2-hydroxyethoxy)-3-methoxybenzamidewith MeMgBr in THF, and by closely following a synthetic route, whichclosely follows that described for preparation of 119. LCMS: m/z 505.15[M+H]⁺.

Individual enantiomers of 120 (120a and 120b) were obtained by SFCseparation of a racemic mixture of 120. +ESI-MS: m/z 505.1 [M+H]⁺.

Compound 121 was prepared usingN-(2-(6-(3-chloro-4-fluorophenyl)pyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(2-(methylamino)-2-oxoethoxy)benzamidewith MeMgBr in THF, and by following a synthetic route, which closelyfollows that described for preparation of 119. LCMS: m/z 502.05 [M+H]⁺.

Compounds 122, 123, 124, 125, 126 and 127 were prepared usingN-(2-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3-methoxybenzamidewith different Grignard reagents in THF, and by following a syntheticroute, which closely follows that described for preparation of 119. 122:LCMS: m/z 521.15 [M+H]⁺. 123: LCMS: m/z 533.15 [M+H]⁺. 124: LCMS: m/z531.10 [M+H]⁺. 125: LCMS: m/z 535.15 [M+H]⁺. 126: LCMS: m/z 519.15[M+H]⁺. 127: LCMS: m/z 517.05 [M+H]⁺.

Individual enantiomers of 122 (122a and 122b) were obtained by SFCseparation of a racemic mixture of 122.

Compound 128 was prepared usingN-(2-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(1H-pyrazol-1-yl)benzamidewith MeMgBr in THF, and by following a synthetic route, which closelyfollows that described for preparation of 119. LCMS: m/z 511.10 [M+H]⁺.

Example 9 Preparation of Compound 129

A 50 mL flask with a magnetic stirring bar was charged with 10-1 (223mg, 1.0 mmol), Weinreb amide (10-2, 282 mg, 1.0 mmol), and THF (10 mL)under N2 atmosphere. The solution was treated with i-PrMgCl (1.3 M, 2.0eq.) dropwise at r.t. The mixture was stirred for 1 h at r.t. Water (50mL) and EA (50 mL) were added. The organic layer was separated and theaqueous phase extracted with EA. The combined organic layers were driedwith MgSO₄ and the volatiles were removed under reduced pressure. Theresidue was purified by column chromatography on silica gel (PE) toprovide 10-3 as a solid (332 mg, 90%). +ESI-MS: m/z 367.0, 369.0 [M+H]⁺.

To a stirred solution of 10-3 (368 mg, 1.0 mmol) in MeOH/THF (5 mL/5 mL)was added NaBH₄ (380 mg, 10 mmol) in portions until the startingmaterials was consumed. The volatiles were removed under reducedpressure. The residue was purified by column chromatography on silicagel (PE:EtOAc=2:1) to give 10-4 as a colorless oil (370 mg, 100%).+ESI-MS: m/z 369.0, 371.0 [M+H]⁺.

A 50 mL flask with a magnetic stirring bar was charged with 10-4 (165mg, 0.5 mmol), 2-(7-fluorobenzo[b]thiophen-3-yl)-dioxaborolane (278 mg,1.0 mmol), Pd(dppf)Cl₂ (8 mg, 1 mol %), KF (180 mg, 3.0 mmol), anddioxane/H₂O (20 mL/5 mL) under N₂ atmosphere. The mixture was stirredfor 10 h at 100° C. Water (50 mL) and EA (50 mL) were added. The organiclayer was separated and the aqueous phase extracted with EA. Thecombined organic phases were dried with MgSO₄ and the volatiles wereremoved under reduced pressure. The residue was purified by columnchromatography on silica gel to provide 129 as a white solid (176 mg,80%). +ESI-MS: m/z 463.9 [M+Na]⁺.

Compound 130 was obtained following the procedure for obtaining 129 byusing 10-2,1,3-dibromoimidazo[1,5-a]pyridine and2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas the starting materials, and then the oxidizing reagent DMP. Compound130 was obtained as a white solid. +ESI-MS: m/z 489.8 [M+H]⁺.

Compound 131 (176 mg, 80%) was obtained following the procedure forobtaining 129 by using 10-2, 4-chloro-2-iodo-6-methoxypyrimidine and2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.+ESI-MS: m/z 483.9 [M+H]⁺.

Example 10 Preparation of Compound 132

Compound 11-1 was prepared using 10-2,2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and3,4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide, and byfollowing a synthetic route, which closely follows that described forpreparation of 129.

Compound 11-1 (402 mg, 0.62 mmol) was dissolved in TFA/DCM (1/1, 6 mL),and stirred at r.t. for 3 h. The solvent was removed and the residue waspurified by column (DCM/MeOH=50:1 to 20:1) on silica gel to give 132(149 mg, 72.4%). +ESI-MS: m/z 442.1[M+H]⁺.

Compound 133 was prepared using 2,4,5-tribromo-1-methyl-1H-imidazole and3,4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide, and byfollowing a synthetic route, which closely follows that described forpreparation of 129. +ESI-MS: m/z 455.9[M+H]⁺.

Compound 134 was prepared using 2,4-dibromothiazole and3,4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide, and byfollowing a synthetic route, which closely follows that described forpreparation of 129. +ESI-MS: m/z 459.0 [M+H]⁺.

+ESI-MS: m/z 502.9 [M+H]⁺.

Example 11 Preparation of Compounds 136 and 137

A mixture of 12-1 (3.26 g, 9.80 mmol), (1R,2R)-2-aminocyclopentan-1-olhydrochloride (1.04 g, 7.55 mmol), EDC (2.17 g, 11.3 mmol), HOBT (1.53g, 11.3 mmol) and TEA (2.60 mL, 18.9 mmol) in DCM (50 mL) was stirred atr.t. for 18 h. The mixture was washed twice with 1M aq. HCl solution,dried (Na₂SO₄), filtered and concentrated under reduced pressure.Chromatography of the residue (cyclohexane-EtOAc, 100:0 to 0:100)afforded 12-2 as a white solid (2.98 g, 95%). UPLC/MS(ES⁺): m/z 416.29[M+H]⁺.

Dess-Martin periodinane (4.55 g, 10.7 mmol) was added to a solution of12-2 (2.98 g, 7.16 mmol) in DCM (50 mL). The mixture was stirred at r.t.for 1.5 h. A 1:1 mixture of 10% aq. Na₂S₂O₃ solution and sat. aq. NaHCO₃solution was added, and the mixture was stirred for 40 mins. The layerswere separated and the organic portion was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane-EtOAc, 100:0 to 0:100) afforded 12-3 as a white solid (2.86g, 96%). UPLC/MS(ES⁺): m/z 413.18 [M+H]⁺.

n-Butyllithium (1.6M solution in hexane, 1.50 mL, 2.42 mmol) was addeddropwise to a stirred solution of 12-4 (760 mg, 2.42 mmol) in toluene(15 mL), which had been pre-cooled to −78° C. After 20 mins, a solutionof 12-3 (500 mg, 1.21 mmol) in THF (10 mL) was added. The mixture wasstirred at −78° C. for 30 mins. The mixture was allowed to warm to r.t.and then quenched with MeOH. The volatiles were removed under reducedpressure. The residue was partitioned between EtOAc and water. Thelayers were separated and the organic portion was dried with Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (water:CH₃CN 100:0 to 95:5) toafford 12-5 as a 2:1 diastereomeric mixture (470 mg, 65%). UPLC/MS(ES⁺):m/z 601.22 [M+H]⁺.

A mixture of (3-chloro-4-fluorophenyl)boronic acid (50.5 mg, 0.290mmol), 12-5 (70 mg, 0.116 mmol), Pd(dppf)Cl₂ (4.3 mg, 0.006 mmol) andaq. Na₂CO₃ (2M solution, 174 uL, 0.348 mmol) in DCE (2 mL) was degassedand heated to 85° C. After 1 h, water was added and the aqueous phasewas extracted with DCM. The organic phase was dried with Na₂SO₄,filtered and concentrated under reduced pressure. The residue wasdissolved in a 10:1 DCM-TFA solution (3 mL) and the mixture was stirredat r.t. for 30 mins. A 1M aq. NaOH solution was added and the mixturewas stirred for further 30 mins. The phases were separated and theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (DCM-MeOH, 98:2)afforded compounds 136 and 137. 136: UPLC/MS(ES⁺): m/z 531.26 [M+H]⁺.137: UPLC/MS(ES⁺): m/z 531.26 [M+H]⁺.

Example 12 Preparation of Compound 138

Compound 13-1 was obtained following the procedure for obtaining 1 byusing 2,4,6-trichloropyridine,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid.

To a solution of 13-1 (972 mg, 2 mmol) in DME (15 mL) was added 13-2(616 mg, 4 mmol), Pd(dppf)Cl₂ (146 mg, 0.2 mmol) and Cs₂CO₃ (1.3 g, 4mmol). The mixture was stirred for 16 h at 120° C. under N₂. Thereaction solution was filtered and to give a clear solution. Thesolution was extracted with EtOAc (80 mL) and washed with brine (3×20mL). Compound 138 was purification by silica column chromatography usingEA:PE=1:1 as the elute (900 mg, 94%). ESI-MS: m/z 478.9 [M+H]⁺.

Example 13 Preparation of Compound 139

To a solution of 14-1 (495 mg, 1.0 mmol) in MeOH (10 mL) was addedaqueous NaOH (10 mL, 1M). The mixture was stirred for 4 h at 60° C. Thesolution was cooled to r.t., acidified to pH=3 using 1N HCl solution andextracted with EtOAc. The organic phase was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to provide 139 (490 mg, 99%).+ESI-MS: m/z 497.1 [M+H]⁺.

Example 14 Preparation of Compounds 140 and 141

Compound 15-2 was prepared starting from2-chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (15-1) according toprocedures provided in PCT Publication No. WO 2004/039366, published May13, 2004, which is hereby incorporated by reference for the limitedpurpose of its disclosure of the preparation of 15-2.

Dess-Martin periodinane (2.00 g, 4.21 mmol) was added to a stirredsolution of 15-2 (835 mg) in dry DCM (5 mL). The mixture was stirred atr.t. for 40 mins, and quenched with a 1:1 mixture of 2M aq. Na₂S₂O₃solution-sat. aq. NaHCO₃ sol (10 mL). After 30 mins., the layers wereseparated. The organic portion was washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane-EtOAc, 100:0 to 60:40) afforded 15-3 as a whitesolid (250 mg). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 4.53 (s,2H), 7.79 (s, 1H), 9.92 (s, 1H).

Nitromethane (191 uL, 3.54 mmol) and K₂CO₃ (32.5 mg, 0.236 mmol) wereadded to a solution of 15-3 (250 mg, 1.18 mmol) in dry THF (5 mL). Themixture was stirred at r.t. for 30 h and EtOAc was added. The organicportion was washed with water and brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford crude 15-4 (343 mg), whichwas used in the next step. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.36-1.49 (m,6H), 4.45 (s, 2H), 4.68 (dd, J=13.6, 8.5 Hz, 1H), 4.85 (dd, J=13.4, 3.4Hz, 1H), 5.43 (dd, J=8.5, 3.3 Hz, 1H), 7.26 (s, 1H).

NaBH₄ (21.0 mg, 0.550 mmol) was added to a solution of NiCl₂-6H₂O (43.0mg, 0.183 mmol) in MeOH (3 mL). After 30 mins, 15-4 (100 mg, 0.367 mmol)dissolved in MeOH (2 mL) was added, followed by additional solid NaBH₄(28.0 mg, 0.730 mmol). The reaction was monitored by UPLC. Whencomplete, the mixture was filtered through a pad of celite and theorganic portion was concentrated under reduced pressure. The residue waseluted through a SCX-cartridge using MeOH and 2M ML-MeOH solution toafford 15-5. UPLC/MS(ES⁺): m/z 243.10 [M+H]⁺.

A mixture of 15-5,3-methoxy-4-{2-[(4-methoxyphenyl)methoxy]ethoxy}benzoic acid (146 mg,0.440 mmol), EDC (106 mg, 0.550 mmol), HOBT (74 mg, 0.550 mmol) and TEA(101 uL, 0.730 mmol) in DCM (4 mL) was stirred at r.t. for 18 h. Themixture was washed twice with 1M aq. HCl solution. The organic portionwas dried with Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 0:100)afforded 15-6 as a pale yellow wax (90 mg, 44% over two steps).UPLC/MS(ES⁺): m/z 557.30 [M+H]⁺.

Dess-Martin periodinane (172 mg, 0.404 mmol) was added to a solution of15-6 (90 mg, 0.162 mmol) in DCM (4 mL). The mixture was stirred at r.t.for 1 h. A 1:1 sat. aq. NaHCO₃ solution-sat. aq. Na₂S₂O₃ solution wasadded. The mixture was stirred at r.t. for 30 mins and the layers wereseparated. The organic portion was washed with water, dried (Na₂SO₄),filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane-EtOAc, 50:50 to 10:90) afforded 15-7 as a paleyellow wax (70 mg, 78%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 6H),3.83 (s, 3H), 3.86-3.92 (m, 2H), 3.96 (s, 3H), 4.27 (t, J=5.0 Hz, 2H),4.52 (s, 2H), 4.60 (s, 2H), 5.11 (d, J=4.5 Hz, 2H), 6.91 (d, J=8.5 Hz,2H), 6.95 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.41(dd, J=8.3, 1.8 Hz, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.90 (s, 1H).

A mixture of 15-7 (90.0 mg, 0.126 mmol),(3-chloro-4-fluorophenyl)boronic acid (55.0 mg, 0.316 mmol), Pd(dppf)Cl₂(6.0 mg, 0.008 mmol) and aq. Na₂CO₃ (2M solution, 190 uL, 0.378 mmol) inDCE (3 mL) was degassed and heated to 85° C. After 20 h, the volatileswere removed under reduced pressure. Chromatography of the residue(cyclohexane-EtOAc, 80:20 to 0:100) afforded the PMB-ether (51 mg). ThePMB-ether was dissolved in DCM (1.5 mL) and treated with TFA (200 uL).The mixture was stirred at r.t. for 30 mins and quenched with 2M aq.NaOH solution. The layers were separated and the aqueous portion wasextracted with DCM. The combined organic portions were dried (Na₂SO₄),filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane-EtOAc, 80:20 to 0:100) afforded 140 as a whitesolid (20 mg, 30% over two steps). ¹H NMR (400 MHz, CDCl₃) δ ppmUPLC/MS(ES⁺): m/z 529.15 [M+H]⁺.

Coupling of 15-7 with7-fluoro-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-indolefollowed removal of all protecting groups (TFA-DCM) afforded 141 as anoff-white solid (9% over two steps). UPLC/MS(ES⁺): m/z 534.33 [M+H]⁺.

Example 15 Preparation of Compound 142

MeMgBr (0.7 mL, 2 mmol) was added dropwise to a stirred solution of 16-1(700 mg, 0.3 mmol) in THF (5 mL) at −78° C. After 1 h, the mixture wasallowed to warm to r.t. (approx. 2 h). The reaction was quenched with 1NHCl and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby column on silica gel (PE:EA=10:1) to give 16-2 (350 mg, 41%).

A solution of 16-2 (350 mg, 0.96 mmol) in ammonia (6 mL) and EtOH (3 mL)was stirred at 90° C. for 10 h. The solvent was removed and the crudeproduct was used in next step without purification.

To a solution of 16-4 (73 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1 mL)was added HATU (152 mg, 0.4 mmol), and stirred at 40° C. for 30 mins.Compound 16-3 (100 mg, 0.33 mmol) was added. The mixture was stirred at40° C. for 10 h. The mixture was diluted with water and extracted withEtOAc. The organic layers was washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by prep-HPLC to give 142(60 mg, 39%). +ESI-MS: m/z 488.9 [M+Na]⁺.

Example 16 Preparation of Compound 143

To a solution of 17-2 (132 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1mL) was added HATU (152 mg, 0.4 mmol), and the mixture stirred at 40° C.for 30 mins. Compound 17-1 (100 mg, 0.33 mmol) was added. The mixturewas stirred at 40° C. for 10 h. The mixture was diluted with water andextracted with EtOAc. The organic layers was washed with brine, driedover Na₂SO₄, and concentrated. The crude product was purified by columnon silica gel (PE:EA=1:1) to give 17-3 (60 mg, 32%).

To a solution of 17-3 (60 mg, 0.1 mmol) in DCM (2 mL) and H₂O (0.2 mL)was added DDQ (45 mg, 0.2 mmol). The mixture was stirred for 2 h. atr.t. The mixture was dissolved in DCM (30 mL). The solution was washedwith sat. NaHCO₃, dried over Na₂SO₄, and concentrated. The residue waspurified by prep-HPLC to give 143 (30 mg, 60%). +ESI-MS: m/z 496.9[M+H]⁺.

Example 17 Preparation of Compound 144

To a solution of 4(5)-methylimidazole (2 g, 24 mmol) in CH₂Cl₂ (150 mL)was added bromine (2.5 mL, 48 mmol) at 0° C. The solution was stirredfor 1H at r.t. The product was filtered and partitioned between EA andsat. NaHCO₃. The product was precipitated from MeOH/CH₂Cl₂ to provide18-1 (4.31 g, 75%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.06 (s, 3H).

To a solution of 18-1 (3.6 g, 15 mmol) and K₂CO₃ (4.1 g, 30 mmol) in DMF(18 mL) was added iodomethane (1.4 mL, 23 mmol) at 25° C. The solutionwas stirred for 15 h. The mixture was poured into water and extractedwith EA The combined organic phase was dried over anhydrous Na₂SO₄, andthe residue was purified by chromatography on silica gel (EA/hexane) togive 18-2 (1.6 g, 41%). ¹H NMR (400 MHz, CDCl₃): δ 3.52 (s, 3H), 2.21(s, 3H).

To a solution of methyl vanillate (7.06 g, 39 mmol) and K₂CO₃ (10.7 g,78 mmol) in DMF (25 mL) was added 1-bromo-2-fluoroethane (4.3 mL, 58mmol) at 25° C. The solution was stirred for 2 days. The mixture waspoured into water and extracted with EA. The combined organic layerswere dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by chromatography on silica gel (EA/hexane) to give 18-3 (8.92g, 103%)). ¹H NMR (400 MHz, CDCl₃): δ 7.63 (dd, J=2.15, 8.41, 1H), 7.55(d, J=8.41, 1H), 4.72-4.86 (m, 2H), 4.27-4.35 (m, 2H), 3.90 (s, 3H),3.88 (s, 3H).

To a solution of 18-3 (8.92 g, 39 mmol) in MeOH (150 mL) was added 2 NNaOH (40 mL, 78 mmol). The solution was stirred for 2 h at 70° C. Themixture was concentrated, acidified with 2N HCl and extracted with EA toprovide 18-4. (5.0 g, 30%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.47 (dd,J=1.96, 8.41, 1H), 7.38 (d, J=1.96, 1H), 6.99 (d, J=8.41, 1H), 4.61-4.76(m, 2H), 4.17-4.27 (m, 2H).

To a solution of 18-4 (3.07 g, 14.3 mmol), glycine methyl ester HCl salt(3.6 g, 29 mmol), HATU (6.5 g, 17 mmol) in DMF (15 mL) was added DIE A(10 mL, 57 mmol). The solution was stirred for 18 h at r.t. The mixturewas diluted with EA. The organic phase was washed with water, 1N HCl,NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated. Theresidue was purified by chromatography on silica gel (EA/hexane) to give18-5 (2.02 g, 51%). ¹H NMR (400 MHz, CDCl₃): δ 7.43 (d, J=2.15, 1H),7.30 (dd, J=2.15, 8.42), 6.90 (d, J-8.42, 1H), 6.57 (br. t, 1H),4.72-4.85 (m, 2H), 4.22-4.35 (m, 2H), 4.25 (d, J=5.08, 2H) 3.85 (s, 3H),3.79 (s, 3H).

To a solution of 18-5 (2.02 g, 7.1 mmol) in MeOH (50 mL) was added 2 NNaOH (10 mL, 20 mmol). The solution was stirred for 2 h at r.t. Themixture was concentrated, acidified with 2N HCl and extracted with EA toprovide 18-6. (1.38 g, 72%). ¹H NMR (400 MHz, CD₃OD): δ 7.49 (m, 2H),7.04 (d, J=8.42, 1H), 4.62-4.85 (m, 2H), 4.25-4.34 (m, 2H), 4.08 (s,2H), 3.90 (s, 3H).

To a solution of 18-6 (0.52 g, 1.9 mmol), N,O-dimethylhydroxylaminehydrochloride (0.23 g, 3.8 mmol), EDCI (0.38 g, 2.3 mmol) in DMF (3 mL)was DIEA (1.0 mL, 5.8 mmol). The solution was stirred for 2 h at r.t.The mixture was diluted with EA. The organic phase was washed withwater, 1N HCl, NaHCO₃ and brine, dried over anhydrous Na₂SO₄, andconcentrated. The residue was purified by chromatography on silica gel(EA/hexane) to give 18-7 (0.28 g, 47%). ¹H NMR (400 MHz, CDCl₃): δ 7.43(d, J=1.96, 1H), 7.33 (dd, J=1.96, 8.22, 1H), 6.90 (d, J=8.22, 1H),4.71-4.84 (m, 2H), 4.26-4.36 (m, 4H), 3.91 (3, 3H), 3.76 (s, 3H), 3.25(s, 3H).

Isopropylmagnesium chloride (2.0M, 0.48 mL, 0.95 mmol) was addeddropwise to a solution of 18-7 (0.12 g, 0.38 mmol) and 18-2 (0.13 g,0.50 mmol) in THF (1.0 mL). The solution was stirred for 2 h at r.t. Thereaction was quenched with 1N HCl, diluted with EA and washed withbrine. The organic solution was filtered to 18-8 (0.030 g, 20%). ¹H NMR(400 MHz, CDCl₃): δ 7.49 (d, J=2.15, 1H), 7.38 (dd, J=2.15, 8.21, 1H),7.03 (t, J=5.09, 1H), 4.93 (d, J=5.09, 2H), 4.74-4.96 (m, 2H), 4.28-4.37(m, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.22 (s, 3H).

A solution of 18-8 (30 mg, 0.070 mmol), 3-chloro-4-fluorophenylboronicacid (24 mg, 0.14 mmol), potassium acetate (21 mg, 0.21 mmol) andPd(dppf)Cl₂ (10 mg, 0.014 mmol) was heated under microwave irradiationfor 1 h at 110° C. The mixture was concentrated and purified bychromatography on silica gel (EA/hexane) to give 18-9 (24 mg, 72%).LCMS: m/z 478.10 [M+H]⁺.

Methylmagnesium bromide (0.33 mL, 0.46 mmol) was added to a solution of18-9 (22 mg, 0.046 mmol) in THF (1.0 mL). The mixture was stirred for 2h at r.t., and then quenched with 1M HCl. The mixture was extracted withEA, washed with brine, dried and concentrated. The residue purified byreverse phase HPLC to give 144 (3.8 mg, 17%). LCMS: m/z 494.15 [M+H]⁺.

Example 18 Preparation of Compound 145

To a solution of 4(5)-methylimidazole (2 g, 24 mmol) in CH₂Cl₂ (150 mL)was added bromine (2.5 mL, 48 mmol) at 0° C. The solution was stirredfor 1H at r.t. The product was filtered and partitioned between EA andsat. NaHCO₃. The product was precipitated from MeOH/CH₂Cl₂ to provide19-1 (4.31 g, 75%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.06 (s, 3H).

To a solution of 19-1 (3.6 g, 15 mmol) and K2CO₃ (4.1 g, 30 mmol) in DMF(18 mL) was added iodomethane (1.4 mL, 23 mmol) at 25° C. The solutionwas stirred for 15 h. The mixture was poured into water and extractedwith EA The combined organic phase was dried over anhydrous Na₂SO₄, andthe residue was purified by chromatography on silica gel (EA/hexane) togive 19-2 (1.6 g, 41%). ¹H NMR (400 MHz, CDCl₃): δ 3.52 (s, 3H), 2.21(s, 3H).

Compound 145 was prepared using iodoethane and closely following theprocedure for preparing of 144. LCMS: m/z 476.10 [M+H]⁺.

Example 19 Preparation of Compound 146

To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g, 1.6 mmol), 20-1(0.485 g, 1.6 mmol), HATU (0.75 g, 2.0 mmol) in DMF (3 mL) was addedDIEA (0.71 mL, 4.1 mmol). The solution was stirred for 18 h at r.t. Themixture was diluted with EA. The organic phase was washed with water, 1NHCl, NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated.The residue was purified by chromatography on silica gel (MeOH/CH₂Cl₂)to give 20-2 (0.176 g, 51%). ¹H NMR (400 MHz, CDCl₃): δ 7.99 (dd,J=2.15, 7.24, 1H), 7.81-7.85 (m, 1H), 7.75 (d, J=8.02, 1H), 7.37-7.42(m, 2H), 7.26-7.27 (m, 1H), 7.25 (t, J=8.71, 1H), 6.93 (dd, J=1.96,8.02), 6.83-6.86 (m, 1H), 4.97-4.99 (m, 1H), 3.99-4.13 (m, 1H), 3.90 (s,3H), 3.89 (s, 3H), 3.54-3.72 (m, 1H).

A solution of 20-2 (25 mg, 0.045 mmol), pyridine-3-boronic acid (11 mg,0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)Cl₂ (6 mg,0.009 mmol) in DME (0.5 mL) and H₂O (0.05 mL) was heated under microwaveirradiation for 1 h at 110° C. The mixture was concentrated and purifiedby chromatography on silica gel (MeOH/CH₂Cl₂) to give 20-3 (22 mg, 88%).¹H NMR (400 MHz, CDCl₃): δ 8.74-8.90 (br. s, 1H), 8.60-8.72 (br. s, 1H),8.00, dd, J=2.15, 7.24), 7.85-7.88 (m, 2H), 7.34-7.45 (m, 5H), 7.17, (t,J=8.80, 1H), 6.94-6.97 (m, 1H), 4.98-5.01 (m, 1H), 4.00-4.09 (m, 1H),3.88 (s, 3H), 3.82 (s, 3H0, 3.68-3.75 (m, 1H).

Dess-Martin periodinane (25 mg, 0.061 mmol) was added to a solution of20-3 (22 mg, 0.043 mmol) in CH₂Cl₂, and stirred for 2 h. The mixture wasdiluted with CH₂Cl₂, washed with sat. Na₂CO₃, and brine, dried overMgSO₄, and concentrated under reduced pressure. The crude product waspurified by chromatography on silica gel (EA/hexane) to give 20-4 (6.1mg, 28%). LCMS: m/z 506.10 [M+H]⁺.

Methylmagnesium bromide (1.4 M in THF, 0.39 mL, 0.39 mmol) was added toa solution of 20-4 (20 mg, 0.039 mmol) in THF (1.0 mL) and stirred for 2h. The mixture was diluted with quenched with 1N HCl and extracted withEA. The organic extracts were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The crude product purified byreverse phase HPLC to provide 146 (0.9 mg, 4%). LCMS: m/z 522.15 [M+H]⁺.

Compound 147 was prepared using pyridine-4-boronic acid pinacol ester inthe Suzuki reaction and by following a synthetic route, which closelyfollows that described for preparation of 146. LCMS: m/z 522.15 [M+H]⁺.

Example 20 Preparation of Compound 148

To a solution of 21-1 (100 mg, 0.549 mmol), HATU (208 mg, 0.549 mmol)and DIPEA (142 mg, 1.1 mmol) in anhydrous DMF (2 mL) was added 21-2 (100mg 0.347 mmol) at 25° C. The solution was stirred for 10 h at thistemperature and then diluted with 1.0 N aqueous NaHCO₃ solution (2×40mL), extracted with EA (2×20 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The residue was purified on a silica gel column togive 21-3 (100 mg, 40.3%). +ESI-MS: m/z 433.1 [M+H]⁺.

To a solution of 21-3 (100 mg, 0.22 mmol) in THF (2 mL) were added Ag₂O(20 mg) and CH₃I (100 mg, 0.72 mmol). The mixture was stirred for 15 hat 40° C. The solid was removed, and the filtrate was concentrated. Theresidue was purified by prep-HPLC (FA) to give 148 as a white solid (40mg, 38.8%). +ESI-MS: m/z 466.9 [M+H]⁺.

Example 21 Preparation of Compound 149

To a solution of 22-1 (1.1 g, 3.1 mmol) in DCM (3 mL) was added DAST(1.4 g; 8.7 mmol). The solution was stirred at r.t. for 1 h with TLCmonitoring. The reaction was quenched with aq. NaHCO₃ at 0° C. andextracted with DCM. The combined organic solution was dried overanhydrous MgSO₄, and evaporated under reduced pressure. The residue waspurified on a silica gel column (PE:EA=20:1 to 6:1) to give 22-2 (0.8g).

To a solution of 22-2 (0.8 g, 2.2 mmol) in DMSO (5 mL) was added NaN₃(300 mg 4.6 mmol). The solution was stirred at 60° C. for 3 h with LCMSmonitoring. The reaction was quenched with aq. NaHCO₃ and extracted withEA. The combined organic solution was dried over anhydrous MgSO₄, andevaporated under reduced pressure to give crude 22-3 (0.7 g), which wasused in next step directly without purification.

To a solution of 22-3 (0.7 g, 2.1 mmol) in EtOH (10 mL) and HCl (2drops, 1.0 N) was added Pd/C (10%, 400 mg) under N₂. The suspension wasdegassed under vacuum and purged with H₂ 3 times. The mixture wasstirred under H₂ (40 psi) at r.t. for 1 h. The suspension was filteredthrough a pad of Celite and the pad cake was washed with EtOH. Thecombined filtrates were concentrated to give crude 22-4 (0.4 g) used fornext step directly without purification

To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (212 mg, 1.0mmol), HATU (570 mg, 1.5 mmol) and DIPEA (322 g, 2.5 mmol) in anhydrousDCM (5 mL) was added 22-4 (298 mg, 1.0 mmol) at 25° C. The solution wasstirred for 3 h. at this temperature, diluted with 1.0 N aqueous NaHCO₃solution, and extracted with DCM. The combined organic layers werewashed by brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The residue was purified by prep-HPLC to give 149 (180mg) as a white solid. +ESI-MS: m/z 493.0 [M+H]⁺.

Compound 150 was prepared using6-(2-bromo-1,1-difluoroethyl)-2-(3-chloro-4-fluorophenyl)-3-methoxypyridine,and by following a synthetic route, which closely follows that describedfor preparation of 149. +ESI-MS: m/z 510.9 [M+H]⁺.

Example 22 Preparation of Compound 151

To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) intoluene (2 mL) was added pyrrolidinone (150 mg, 1.7 mmol), potassiumphosphate (0.55 g, 2.2 mmol), xantphos (25 mg, 0.43 mmol) andtris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.43 mmol). The mixturewas heated at 110° C. for 3 h. The mixture was then diluted with EA. Theorganic phase was washed with water, 1N HCl, NaHCO₃ and brine, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified bychromatography on silica gel (EA/hexane) to give 23-1 (0.178 g, 83%).LCMS: m/z 478.10 [M+H]⁺.

To a solution of 23-1 (0.178 g, 0.72 mmol) in methanol (6 mL) was addedNaOH (2.0 M, 2.0 mL) at 25° C. The solution was stirred for 15 h,acidified with 2N HCl and extracted with EA. The combined organic phasewas dried over anhydrous Na₂SO₄ to give 23-2 (0.152 g, 90%). ¹H NMR (400MHz, CDCl₃): δ 7.52 (dd, J=1.77, 8.22 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H),7.30 (d, J=8.22 Hz, 1H), 3.82 (s, 3H), 3.75 (t, J=7.04 Hz, 2H), 2.55 (t,J=8.02 Hz, 2H), 2.0-2.3 (m, 2H).

To a solution of 23-2 (0.152 g, 0.65 mmol), 23-3 (0.19 g, 0.65 mmol),HATU (0.37 g, 0.97 mmol) in DMF (1 mL) was added DIEA (0.23 mL, 1.3mmol). The solution was stirred for 2 h at r.t. The mixture was dilutedwith EA. The organic phase was washed with water, 1N HCl, NaHCO₃ andbrine, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by chromatography on silica gel (EA/hexane) to give 23-4 (0.172g, 51%). LCMS: m/z 478.10 [M+H]⁺.

Dess-Martin periodinane (220 mg, 0.50 mmol) was added to a solution of23-4 (172 mg, 0.34 mmol) in CH₂Cl₂, and the mixture was stirred for 2 h.The mixture was diluted with CH₂Cl₂ and washed with sat. Na₂CO₃, andbrine, dried over MgSO₄, and concentrated under reduced pressure. Thecrude product was purified by chromatography on silica gel (EA/hexane)to give 23-5 (77 mg, 45%) as white solid. LCMS: m/z 512.10 [M+H]⁺.

Methylmagnesium bromide (1.0 mL, 1.4 mmol) was added to a solution of23-5 (72 mg, 0.14 mmol) in THF (1.0 mL). The mixture was stirred for 2 hat r.t., and then quenched with 1N HCl. The mixture was extracted withEA, washed with brine, dried and concentrated. The residue purified byreverse phase HPLC to give 151 (6.5 mg, 17%) as white solid. LCMS: m/z528.15 [M+H]⁺.

Example 23 Preparation of Compound 152

To a stirring mixture of 24-1 (44 mg, 0.197 mmol) in DMF were added HATU(83 mg, 0.218 mmol) and DIPEA (51 mg, 0.4 mmol). The mixture was stirredat r.t. for 10 mins and a solution of2-amino-1-(6-bromo-5-methoxypyridin-2-yl)ethan-1-ol was added. Themixture was stirred at r.t. for 1 h, diluted with EtOAc and quenchedwith a sat. NaHCO₃ solution. The mixture was stirred at r.t. for 10 minsand the layers were separated. The aqueous layer was extracted withEtOAc. The organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude product was purified via silica gelchromatography to afford 24-2. LCMS: m/z 451.05 [M+H]⁺.

To a stirring mixture of 24-2 (28 mg, 0.062 mmol) in DME/water (10:1,2.2 mL) were added Cs₂CO₃ (60 mg, 0.19 mmol), PdCl₂ppf (10 mg, 0.012mmol), and (3-chloro-4-fluorophenyl)boronic acid (11 mg, 0.062 mmol).The mixture was stirred under microwave conditions at 110° C. for 1 h.The crude product mixture was cooled to r.t. and concentrated underreduced pressure. The crude mixture was purified via silica gelchromatography to afford 152. LCMS: m/z 501.15 [M+H]⁺.

Compounds 153 and 154 were prepared using commercially available benzoicacids and 2-amino-1-(6-bromo-5-methoxypyridin-2-yl)ethan-1-ol in 2 or 3steps, and by following a synthetic route, which closely follows thatdescribed for preparation of the compound of Example 23. 153: LCMS: m/z497.05 [M+H]⁺. 154: LCMS: m/z 475.10 [M+H]⁺.

Example 24 Preparation of Compound 155

To a solution of 25-1 (1.82 g, 10 mmol) and K₂CO₃ (2.76 g, 20 mmol) inCH₃CN (20 mL) at r.t. was slowly added 2-bromoacetonitrile (2.4 g, 20mmol). The mixture was heated to reflux and stirred for 15 h. Thesolvent were removed under reduced pressure. Purification by columnchromatography on silica gel (PE:EA=3:1) provided 25-2 (2 g, 90%).

To a solution of 25-2 (2.21 g, 10 mmol) in methanol (10 mL) was addedNaOH aqueous (10 mL, 1M). The mixture was stirred for 4 h at 60° C. Thesolution was cooled to r.t., acidified to pH=4 using 1N HCl solution andextracted with EtOAc. The organic phase was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to provide 25-3 (1.1 g, 50%).

To a solution of 25-3 (226 mg, 0.1 mmol) in DMF (3 mL) were added HATU(570 mg, 1.5 mmol) and DIPEA (387 mg, 3 mmol) at r.t. The solution wasstirred for 10 mins at r.t. Compound 25-4 (287 mg, 1 mmol) was added andstirred for 1 h. The solution was extracted with EtOAc and washed withH₂O. The organic phase was concentrated and purified by prep-TLC to give155 (200 mg, 40%). +ESI-MS: m/z 495.9 [M+H]⁺.

Example 25 Preparation of Compound 156

To a stirring mixture ofN-(2-(6-(7-fluorobenzo[b]thiophen-3-yl)-4-methylpyridin-2-yl)-2-oxoethyl)-3,4-dimethoxybenzamide(20 mg, 0.043 mmol) in EtOH (0.25 mL) were added methoxy aminehydrochloride (4 mg, 0.048 mmol) followed by an addition of pyridine (34mg, 0.43 mmol). The mixture was heated at 80° C. for 30 mins and thencooled to r.t. The mixture was concentrated under reduced pressure. Thecrude mixture was purified via prep-HPLC to afford 156. LCMS: m/z 494.10[M+H]⁺.

Compound 157 was prepared usingN-(2-(6-(7-fluorobenzo[b]thiophen-3-yl)pyridin-2-yl)-2-oxoethyl)-3,4-dimethoxybenzamideand hydroxylamine hydrochloride, and by following a synthetic route,which closely follows that described for preparation of 156. LCMS: m/z466.25 [M+H]⁺.

Example 26 Preparation of Compound 158

To a stirring mixture of 158 (20 mg, 0.036 mmol) in THF (1 mL) wereadded bis(tri-/c/7-butylphosphine)palladium(0) (3.6 mg, 0.008 mmol), anda solution of MeZnCl in THF (0.055 mL, 0.11 mmol). The mixture wasstirred under microwave condition at 100° C. for 1 h. The mixture wascooled to r.t., diluted with EtOAc and slowly quenched with a sat. NH₄Clsolution. The mixture was stirred at r.t. for 20 mins and then thelayers were separated. The aqueous layer was extracted with EtOAc. Theorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude product mixture was purified via silica gelcolumn to afford 159 as a colorless oil. LCMS: m/z 495.1 [M+H]⁺.

Example 27 Preparation of Compound 160

To a stirring mixture of 26-1 (50 mg, 0.082 mmol) in MeOH (1 mL) wereadded ammonium acetate (94 mg, 1.23 mmol), NaCNBH₃ (7.7 mg, 0.12 mmol).The mixture was heated at 70° C. for 1 h and then cooled to roomtemperature. The mixture was diluted with EtOAc and slowly quenched witha sat. NH₄Cl solution. The aqueous layer was extracted with EtOAc. Theorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude product mixture was purified via silica gelchromatography to afford 26-2. The PMB ether was removed using TFA inDCM at r.t. The crude product was concentrated under reduced pressureand purified via prep-HPLC to afford 160 (3.1 mg) as a white solid.LCMS: m/z 490.15 [M+H]⁺.

Example 28 Preparation of Compound 161

To a solution of 3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoicacid (205 mg, 0.62 mmol) in DMF (15 mL) were added DIPEA (320 mg, 2.48mmol) and HATU (235.6 mg, 0.62 mmol). The mixture was stirred at r.t.for 30 mins, and 27-1 (195 mg, 0.62 mmol) was added. The mixture wasstirred at r.t. overnight. The mixture was diluted with water andextracted with EA. The organic layer was dried over sodium sulfate, andconcentrated in vacuum to give the crude product, which was purified bycolumn chromatography to give 27-2 (180 mg). +ESI-MS: m/z 631.1 [M+H]⁺.

Compound 27-2 (180 mg, 0.286 mmol) was dissolved in TFA/DCM (10 mL). Themixture was stirred at r.t. for 1 h (monitored by TLC). The mixture wasextracted with EA, and washed with a sat. NaHCO₃ solution. The organiclayer was dried over sodium sulfate, and concentrated in vacuum to givethe crude product, which was purified by prep-HPLC to give 161 (50 mg)as a white solid. +ESI-MS: m/z 511.1 [M+H]⁺.

Example 29 Preparation of Compound 162

A solution of 28-1 (2.59 g, 0.01 mol) in NH₃/MeOH (20 mL) was stirred atr.t. for 30 mins. The solvent was removed by rotary evaporator. Theresidue, 28-2, was used in next step.

A mixture of 28-2 (2.44 g, 0.01 mol) 28-3 (2.73 g, 0.01 mol) and AgSbF₆(5.14 g, 0.015 mol) in DME (20 mL) was stirred for 2 h at 120° C. undermicrowave irradiation. The mixture was filtered. The filtrate wasconcentrated by rotary evaporator to give crude 28-4 (5 g), which wasused in next step without further purification.

To a solution of 28-4 (5 g) in EtOAc (10 mL) was added HCl-EtOAc (30mL). The solution was stirred for 10 h. The solvent was concentrated byrotary evaporator. The product was purified by prep-HPLC to give 28-5(250 mg). ESI-MS: m/z 278.8 [M+H]⁺.

To a solution of 28-5 (145 mg, 0.8 mmol) in DMF (10 mL) was added HATU(343 mg, 0.9 mmol), DIEA (155 mg, 1.2 mmol), and stirred for 5 mins.3,4-dimethoxybenzoic acid (250 mg, 0.8 mmol) was added and the mixturewas stirred for 5 h. Water (100 mL) was poured into the solution, and asolid precipitated. The solid was purified by silica columnchromatography (PE:EA=1:1) to give 162 (158 mg, 45%). ESI-MS: m/z 442.9[M+H]⁺.

Example 30 Preparation of Compound 163

A 50 mL three-necked round bottle flask was charged with a solution of2,6-dibromopyridine (1.15 g, 5 mmol, 5.0 eq.) in THF under nitrogen. Thesolution was cooled to −78° C., and n-BuLi (2 mL, 5 mmol, 5.0 eq.) wasadded dropwise. After addition, the mixture was stirred for 30 mins. Asolution of 29-1 (115 mg, 1.0 mmol, 1.0 eq.) (prepared according toWuitschik et al., J. Med. Chem. (2010) 53(8):3327-3246, which hereby isincorporated by reference for the limited purpose of preparing 29-1) inTHF (3˜5 mL) was added dropwise. After addition, the mixture was stirredfor 30 mins. The reaction was quenched with sat. NH₄Cl, and the mixturewas extracted by EA (3×10 mL). The combined organic phase wasconcentrated to dryness, and the residue was purified by prep-TLC togive 29-2 as a yellow oil (80 mg). ¹H-NMR (400 MHz, CDCl₃), δ=7.67-7.60(m, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.23 (s, 2H),4.99 (d, J=7.0 Hz, 2H), 4.89 (d, J=7.0 Hz, 2H).

A 50 mL round bottom flask was charged with a mixture of 29-2 (0.4 g.1.46 mmol), boric ester (0.6 g, 2.16 mmol, 1.5 eq.), Pd(dppf)Cl₂ (107mg, 0.146 mmol, 0.1 eq.) and Na₂CO₃ (320 mg, 3.0 mmol, 3.0 eq.) indioxane/H₂O (10 mL/2 mL). The mixture was degassed and refilled withnitrogen. The mixture was heated to reflux overnight. The mixture wascooled to r.t. and concentrated to dryness. The residue was purified bycolumn on silica gel (5˜10% EA in PE) to give 29-3 as a pink oil (0.44g, 87% yield). ¹H-NMR (400 MHz, CDCl₃), δ=8.02 (d, J=8.5 Hz, 1H), 7.92(t, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.67 (dd, J=7.8, 14.3 Hz, 2H), 7.42(dt, J=5.5, 8.0 Hz, 1H), 7.16-7.07 (m, 1H), 5.33 (s, 2H), 5.10 (d, J=7.0Hz, 2H), 5.00 (d, J=6.5 Hz, 2H).

A 250 mL round bottom flask was charged with a solution of 29-3 (0.4 g,1.17 mmol) in EtOH (100 mL) and Pd/C (0.2 g). The mixture was stirredunder hydrogen balloon overnight. The mixture was filtered, andconcentrated to dryness. Crude 29-4 was used in the next step withoutfurther purification.

To a solution of 29-4 (270 mg, 0.86 mmol, 1.0 eq.), acid (313 mg, 0.942mmol, 1.1 eq.) and DIEA (0.33 g, 3.0 eq.) in DMF (10 mL) was added HATH(360 mg, 0.942 mmol, 1.1 eq.), and the mixture was stirred at r.t.overnight. The mixture was diluted with EA and water. The organic phasewas washed with brine, dried over anhydrous MgSO₄, and concentrated todryness. The residue was purified by silica gel column (60% EA in PE) togive 29-5 as a pale yellow oil (0.4 g, 74%).

To a solution of 29-5 (0.35 g) in DCM (25 mL) was added TFA (5 mL), andthe mixture was stirred at r.t. for 10 mins. The mixture was neutralizedwith sat. Na₂CO₃ solution. The organic phase was concentrated andpurified by prep-TLC to give 163 as a white solid (70 mg). +ESI-MS: m/z509.0 [M+H]⁺.

Example 31 Preparation of Compound 164

To a solution of 30-1 (190 mg, 0.30 mmol) in THF (5 mL) was added NaBH₄(20 mg, 0.6 mmol) at r.t. MeOH (1 mL) was added, and the mixture wasstirred at 20° C. for 1 h. The residue was purified by columnchromatography on silica gel (PE) to provide 30-2 (190 mg, 99%).

To a solution of 30-2 (190 mg, 0.3 mmol) in DCM (3 mL) was added TFA(0.5 mL) and H₂O2 (0.2 mL, 30%, 2eq), and the mixture was stirred for 30mins. The mixture was neutralized with a sat. NaHCO₃ solution, andextracted with DCM (3×10 mL). The solution was concentrated to give 164in crude form (200 mg), +ESI-MS: m/z 625.0 [M+H]⁺.

Example 32 Preparation of Compound 165

Compound 31-2 (106 mg, 0.5 mmol), 31-1 (140 mg, 0.5 mmol) andtriethylamine (1 mmol) were dissolved in DMF (5 mL). HATU (380 mg, 1mmol) was added to the solution. After 15-30 mins, the mixture wastreated with sat. NaCl solution (100 mL), and extracted with EtOAc (3×10mL). The combined organic phase was washed with 2N HCl solution and 5%NaHCO₃ solution. The organic layer were dried over anhydrous MgSO₄, andconcentrated in vacuum to give the crude product. The crude product waspurified by silica gel column chromatography eluting with EtOAc/PE (1/1)to give 165 as a white solid (24 mg, 10%). +ESI-MS: m/z 483.0 [M+H]⁺.

Example 33 Preparation of Compound 166

Dess-Martin periodinane (1.49 g, 3.52 mmol) was added to a stirredsolution of 32-1 (300 mg, 1.40 mmol) in dry DCM (6.5 mL). The mixturewas stirred at r.t. for 1 h and quenched with a 1:1 mixture of 2M aq.Na₂S₂O₃ solution and sat. aq. NaHCO₃ solution (10 mL). The mixture wasstirred vigorously for 30 mins and the layers were separated. Theorganic portion was washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude aldehyde was progressedto the next step without further purification. The aldehyde wasdissolved in tert-butanol (21 mL). To the solution, 2-methyl-2-butene(1.13 mL, 13.5 mmol) and a solution of sodium chlorite (244 mg, 2.70mmol) and sodium phosphate monobasic dihydrate (1.36 g, 8.70 mmol) inwater (21 mL) were added. The mixture was stirred at r.t. for 18 h.Brine was added and the mixture was extracted 3 times with EtOAc. Thecombined organic portions were dried (Na₂SO₄) and filtered. Thevolatiles were removed under reduced pressure. Acid 32-2 (310 mg) wasprogressed to the next step without further purification. UPLC/MS(ES⁺):m/z 228.07 [M+H]⁺.

1,1′-Carbonyldiimidazole (1.17 g, 7.21 mmol) was added to a solution of32-2 (250 mg) in THF (9.6 mL). The mixture was stirred at r.t. for 30mins and then nitromethane (671 mg, 11.0 mmol) and potassium carbonate(608 mg, 4.40 mmol) were added. After 3 h, the volatiles were removedunder reduced pressure. The residue was taken up with EtOAc. The organicportion was washed with water, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Crude 32-3 (300 mg) was progressedto the next step without further purification. UPLC/MS(ES⁺): m/z 271.05[M+H]⁺.

Methylmagnesium bromide (3M solution in Et₂O, 204 uL, 0.612 mmol) wasadded to a solution of 32-3 (300 mg) in THF (8 mL), which had beenpre-cooled to −40° C. The mixture was stirred at −40° C. for 1 h,allowed to reach r.t. and then quenched with 1M aq. HCl solution. Theaqueous portion was extracted twice with EtOAc. The combined organicportions were dried with Na₂SO₄, filtered and concentrated under reducedpressure. Crude 32-4 was progressed to the next step without furtherpurification. UPLC/MS(ES⁺): m/z 287.10 [M+H]⁺.

NaBH₄ (52.0 mg, 1.38 mmol) was added to a solution of NiCl₂-6H₂O (109mg, 0.460 mmol) in MeOH (10 mL). After 30 mins, nitro-derivative 32-4(250 mg) dissolved in MeOH (2 mL) was added, followed by additionalsolid NaBH₄ (70 mg). The reaction was monitored by UPLC. When complete,the mixture was filtered through a pad of celite and the organic portionwas concentrated under reduced pressure. Crude 32-5 (235 mg) wasprogressed to the next step without further purification. UPLC/MS(ES⁺):m/z 257.17 [M+H]⁺.

A mixture of 32-5 (235 mg),3-methoxy-4-{2-[(4-methoxyphenyl)methoxy]ethoxy}benzoic acid (365 mg,1.10 mmol), EDC (263 mg, 1.38 mmol), HOBT (186 mg, 1.38 mmol) and TEA(255 uL, 1.84 mmol) in DCM (8 mL) was stirred at r.t. for 3 h. Themixture was washed twice with 1M aq. HCl solution. The organic portionwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.Chromatography of the residue (cyclohexane-EtOAc, 60:40 to 10:90)afforded 32-6 as an off-white solid (60 mg, 12% starting from 32-1).UPLC/MS(ES⁺): m/z 571.20 [M+H]⁺.

A mixture of 32-6 (60 mg, 0.100 mmol), (3-chloro-4-fluorophenyl)boronicacid (91.0 mg, 0.500 mmol), Pd(dppf)Cl₂ (3.6 mg, 0.005 mmol) and aq.Na₂CO₃ (2M solution, 0.500 mmol, 250 uL) in DCE (1 mL) was degassed andthen stirred with heat to 85° C. for 4 h. Water and DCM were added, andthe layers were separated. The organic phase was dried with Na₂SO₄,filtered and evaporated. Chromatography of residue (cyclohexane:EtOAc,100:0 to 20:80) afforded 32-7 (46 mg, 69%). UPLC/MS(ES⁺): m/z 665.47[M+H]⁺.

A solution of 32-7 (46.0 mg, 0.069 mmol) in 10:1 DCM-TFA (1.1 mL) wasstirred at room temperature for 1 h. 1M aq. NaOH solution was added andthe mixture was stirred for 15 mins. The layers were separated. Theorganic portion was dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by reverse phasechromatography (water:CH₃CN, 100:0 to 50:50) to afford 166 as a whitesolid (racemic mixture, 18 mg, 33%). UPLC/MS(ES⁺): m/z 545.33 [M+H]⁺.

Example 34 Preparation of Compound 167

To a stirring mixture of 33-1 (40 mg, 0.061 mmol) in THF (1.0 mL) atr.t. under argon was added a solution of MeMgBr (1.4 M) in THF (0.5 mL)dropwise. The mixture was reacted at r.t. for 1 h. The mixture wasdiluted with EtOAc and quenched with a sat. NH₄Cl solution. The mixturewas stirred at r.t. for 10 mins and the layers were separated. Theaqueous layer was extracted with EtOAc. The organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudemixture was purified via silica gel column to afford 33-2 as a whitesolid. LCMS: m/z 669.1 [M+H]⁺.

To a stirring mixture of 33-2 (20 mg, 0.0299 mmol) in DCM (1.0 mL) atr.t. was added dropwise TFA (0.2 mL). The mixture was stirred at r.t.for 10 mins and then concentrated under reduced pressure. The crudeproduct mixture was purified via prep-HPLC to afford 167. LCMS: m/z549.05 [M+H]⁺.

Example 35 Preparation of Compound 168

To a stirring mixture of 2-bromothiazole (0.2 g, 1.22 mmol) in THF underAr at −78° C. was added dropwise a solution of n-BuLi (2.5 M) in hexane(0.49 mL, 1.22 mmol). The mixture was stirred at −78° C. for 15 mins andthen a solution of 34-1 (40 mg, 0.081 mmol) in THF (0.5 mL) was added.The mixture was stirred at −78° C. for 1 h and then warmed to r.t. for10 mins. The mixture was diluted with EtOAc and quenched with a sat.NH₄Cl solution. The mixture was stirred at r.t. for 10 mins and then thelayers were separated. The aqueous layer was extracted with EtOAc (2×15mL). The organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude mixture was purified via silica gelchromatography and further purified via prep-HPLC to afford 168 as a tansolid. LCMS: m/z 576.1 [M+H]⁺.

Example 36 Preparation of Compound 169

To a solution of 34-2 (100 mg, 0.442 mmol), HATU (251 mg, 0.66 mmol) andDIPEA (170 mg, 1.32 mmol) in anhydrous DMF (2 mL) was added 34-3 (127 mg0.442 mmol) at 25° C. The solution was stirred for 10 h at r.t. and thendiluted with 1.0 N aqueous NaHCO₃ solution (2×40 mL), extracted with EA(2×20 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified on a silica gel column to give 169 (120 mg, 54.8%).+ESI-MS: m/z 497.1 [M+H]⁺.

Example 37 Preparation of Compound 170

Compound 170 was prepared using 2,6-dichloro-3-methylpyridine,2-(7-fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3,4-dimethoxybenzoic acid, and by closely following a syntheticroute, which closely follows that described for the preparation of 1.+ESI-MS: m/z 464.9 [M+H]⁺.

Example 38 Preparation of Compounds 171 and 172

To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g, 1.6 mmol), 35-1(0.485 g, 1.6 mmol), HATU (0.75 g, 2.0 mmol) in DMF (3 mL) was addedDIEA (0.71 mL, 4.1 mmol). The solution was stirred for 18 h at r.t. Themixture was diluted with EA. The organic phase was washed with water, 1NHCl, NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated.The residue was purified by chromatography on silica gel (MeOH/CH₂Cl₂)to give 171 (0.176 g, 51%). ¹H NMR (400 MHz, CDCl₃): δ 7.99 (dd, J=2.15,7.24, 1H), 7.81-7.85 (m, 1H), 7.75 (d, J=8.02, 1H), 7.37-7.42 (m, 2H),7.26-7.27 (m, 1H), 7.25 (t, J=8.71, 1H), 6.93 (dd, J=1.96, 8.02),6.83-6.86 (m, 1H), 4.97-4.99 (m, 1H), 3.99-4.13 (m, 1H), 3.90 (s, 3H),3.89 (s, 3H), 3.54-3.72 (m, 1H).

A solution of 171 (25 mg, 0.045 mmol), pyridine-3-boronic acid (11 mg,0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)Cl₂ (6 mg,0.009 mmol) in DME (0.5 mL) and H₂O (0.05 mL) was heated under microwaveirradiation for 1 h at 110° C. The mixture was concentrated and purifiedby chromatography on silica gel (MeOH/CH₂Cl₂) to give 172 (22 mg, 88%).¹H NMR (400 MHz, CDCl₃): δ 8.74-8.90 (br. s, 1H), 8.60-8.72 (br. s, 1H),8.00, dd, J=2.15, 7.24), 7.85-7.88 (m, 2H), 7.34-7.45 (m, 5H), 7.17, (t,J=8.80, 1H), 6.94-6.97 (m, 1H), 4.98-5.01 (m, 1H), 4.00-4.09 (m, 1H),3.88 (s, 3H), 3.82 (s, 3H0, 3.68-3.75 (m, 1H).

Example 39 Preparation of Compound 173

To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) intoluene (2 mL) was added pyrrolidinone (150 mg, 1.7 mmol), potassiumphosphate (0.55 g, 2.2 mmol), xantphos (25 mg, 0.43 mmol) andtris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.43 mmol). The mixturewas heated at 110° C. for 3 h. The mixture was then diluted with EA. Theorganic phase was washed with water, 1N HCl, NaHCO₃ and brine, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified bychromatography on silica gel (EA/hexane) to give 36-1 (0.178 g, 83%).LCMS: m/z 478.10 [M+H]⁺.

To a solution of 36-1 (0.178 g, 0.72 mmol) in methanol (6 mL) was addedNaOH (2.0 M, 2.0 mL) at 25° C. The solution was stirred for 15 h,acidified with 2N HCl and extracted with EA. The combined organic phasewas dried over anhydrous Na₂SO₄ to give 36-2 (0.152 g, 90%). ¹H NMR (400MHz, CDCl₃): δ 7.52 (dd, J=1.77, 8.22 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H),7.30 (d, J=8.22 Hz, 1H), 3.82 (s, 3H), 3.75 (t, J=7.04 Hz, 2H), 2.55 (t,J=8.02 Hz, 2H), 2.0-2.3 (m, 2H).

To a solution of 36-2 (0.152 g, 0.65 mmol), 36-3 (0.19 g, 0.65 mmol),HATU (0.37 g, 0.97 mmol) in DMF (1 mL) was added DIEA (0.23 mL, 1.3mmol). The solution was stirred for 2 h at r.t. The mixture was dilutedwith EA. The organic phase was washed with water, 1N HCl, NaHCO₃ andbrine, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by chromatography on silica gel (EA/hexane) to give 173 (0.172g, 51%). LCMS: m/z 478.10 [M+H]⁺.

Example 40 Preparation of Compound 174

Addition of MeMgBr to 174-1 afforded 174 as a white solid (50%).UPLC/MS(ES⁺): m/z 445.27 [M+H]⁺.

Example 41 Preparation of Compound 175

Addition of MeMgBr to 175-1 afforded 175 as a white solid (10%).UPLC/MS(ES⁺): m/z 497.1 [M+H]⁺.

Example 42

Trimethylsulfoxonium iodide (1.19 g, 5.41 mmol) was added to a solutionof potassium tert-butoxide (551 mg, 4.92 mmol) in DMSO (10 mL). Themixture was stirred at r.t. for 30 mins. A solution ofN-{2-[6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl]-2-oxoethyl}-3-methoxy-4-{2-[(4-methoxyphenyl)methoxy]ethoxy}benzamide(1, 3.00 g, 4.92 mmol) in DMSO (20 mL) was added. The mixture wasstirred at r.t. for 10 mins. The mixture was diluted with EtOAc andwater. The layers were separated, and the aqueous portion was extractedwith EtOAc. The combined organic extracts were washed with brine, driedwith Na₂SO₄ and concentrated under reduced pressure to afford the crudeepoxide 2 (3.34 g). Epoxide 2: UPLC/MS(ES⁺): m/z 623.40 [M+H⁺], Withchromatography (cyclohexane-EtOAc, 75:25 to 50:50), epoxide 2quantitatively rearranged to oxazoline 3 (1.92 g recovered from 3 g ofcrude 2). Oxazoline 3: UPLC/MS(ES⁺): m/z 623.29 [M+H⁺].

Method A: A mixture of epoxide 2 (100 mg, crude) and an amine (10 eq.)in MeOH (1 mL) was stirred at r.t. or heated to 100° C. When complete,the reaction was concentrated under reduced pressure. The residue wasdissolved in a 10:1 DCM:TFA mixture (2.2 mL). After 30 mins of stirringat r.t., a 2M aq. NaOH solution was added. The mixture was stirred atr.t. for 10 mins. The layers were separated, and the aqueous portionextracted with DCM. The combined organic portions were dried withNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof the residue afforded the aminol.

Method B: A mixture of epoxide 2 (150 mg, crude), an amine (2 eq.) andK₂CO₃ (66.0 mg, 2 eq.) in DMF (2 mL) was stirred at 50° C. Whencomplete, the reaction was diluted with EtOAc. The organic portion waswashed twice with water, dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was dissolved in DCM (2 mL) andtreated with TFA (300 uL). After 1 h, the reaction was quenched with 2Maq. NaOH solution. The layers were separated, and the organic portionwas concentrated under reduced pressure. Chromatography of the residueafforded the aminol.

Method C: TEA (270 uL, 1.93 mmol) and MsCl (150 uL, 1.93 mmol) wereadded to a solution of 3 (600 mg, 0.964 mmol) in DCM (4 mL). The mixturewas stirred at r.t. for 2 h. The mixture was poured into 1M aq. HClsolution and extracted with DCM. The combined organic portions weredried with Na₂SO₄ and filtered. The volatiles were removed under reducedpressure to afford the crude mesylate 4, which was directly used in thenext step. A mixture of 4 (80 mg) and an amine (50 uL) in MeOH (2 mL)was heated to 85° C. in a sealed vial. When complete, the reaction wasconcentrated under reduced pressure. The residue was dissolved in MeOH(1.5 mL) and treated with a 6M aq. HCl solution (1.5 mL). The mixturewas heated to 65° C. for 2 h. After cooling to r.t., the mixture waspurified by reverse phase chromatography to afford the aminol.

Method D: A mixture of epoxide 2 (50 mg, crude) and an amine (10 eq.)was heated to 60° C. under microwave irradiation. When complete, thereaction was concentrated under reduced pressure. The residue wasdissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h, thereaction was quenched with 2M aq. NaOH solution. The layers wereseparated, and the organic portion was concentrated under reducedpressure. Chromatography of the residue afforded the aminol.

Example 43 Preparation of Compound 176

Epoxide 2 (200 mg, crude) was dissolved in a 1:1 MeOH:6M aq. HClsolution (2 mL), and the mixture was stirred at 60° C. for 2 h. Themixture was basified with 6M aq. NaOH solution and purified by reversephase chromatography (water:CH₃CN, 100:0 to 50:50) to afford 176 as anoff-white solid (40.2 mg). UPLC/MS(ES⁺): m/z 521.10 [M+H]⁺.

Example 44 Preparation of Compound 177

Reaction of epoxide 2 with a 2M MeNH₂-MeOH solution followed byPMB-group removal according to Method A afforded 177 as a white solid(13% over 3 steps). UPLC/MS(ES⁺): m/z 534.30 [M+H]⁺.

Example 45 Preparation of Compound 178

Reaction of epoxide 2 with a 2M Me₂NH-MeOH solution followed byPMB-group removal according to Method A afforded 178 as a white solid(37% over 3 steps). UPLC/MS(ES⁺): m/z 548.30 [M+H]⁺.

Example 46 Preparation of Compound 179

Reaction of epoxide 2 with a 7M NH₃-MeOH solution followed by PMB-groupremoval according to Method A afforded 179 as a white solid (24% over 3steps). UPLC/MS(ES⁺): m/z 520.40 [M+H]⁺.

Example 47

A solution of 179 (10.0 mg, 0.019 mmol) and triphosgene (5.0 mg, 0.019mmol) in a 1:1 5% aq. NaHCO₃:MeOH mixture (1 mL) was stirred and heatedat 40° C. for 3 h. The volatiles were removed under reduced pressure toafford a 30:70 mixture of 180 and the corresponding methyl carbamate.This mixture was dissolved in DMF (0.5 mL) and treated with NaH (60% oildispersion, 1 mg). After 30 mins, the reaction was quenched with MeOH,and the volatiles were removed under reduced pressure. The residue waspurified by reverse phase chromatography (0.1% HCOOH:water-0.1%HCOOH:CH₃CN, 100:0 to 30:70) to afford 180 as a white solid (4.0 mg,39%). UPLC/MS(ES⁺): m/z 546.30 [M+H]⁺.

Example 48 Preparation of Compound 181

Reaction of epoxide 2 with morpholine followed by PMB-group removalaccording to Method B afforded 181 as a white solid (10% over 3 steps).UPLC/MS(ES⁺): m/z 590.40 [M+H]⁺.

Example 49 Preparation of Compound 182

A mixture of epoxide 2 (100 mg, crude), ketopiperazine (80 mg, 0.80mmol) and K₂CO₃ (155 mg, 1.13 mmol) in DMF (2 mL) was stirred at 60° C.for 18 h. The mixture was diluted with EtOAc, and the organic portionwas washed with water (2×), dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was dissolved in MeOH (2 mL) andtreated with 3M aq. HCl solution (500 uL). The mixture was heated to 80°C. and stirred at 80° C. for 30 mins. The volatiles were removed underreduced pressure. The residue was purified by reverse phasechromatography (water-CH₃CN, 100:0 to 0:100) to afford 182 as a lightyellow solid (14% over 3 steps). UPLC/MS(ES⁺): m/z 603.30 [M+H]⁺.

Example 50 Preparation of Compound 183

Reaction of epoxide 2 with ketopiperazine followed by PMB-group removalaccording to Method B afforded 183 as a light yellow solid (10% over 3steps). UPLC/MS(ES⁺): m/z 621.40 [M+H]⁺.

Example 51 Preparation of Compounds 184, 185 and 186

Reaction of epoxide 2 with pyrazole followed by PMB-group removalaccording to Method B afforded 184 as a racemic mixture (32% over 3steps). This mixture was resolved by using a prep-HPLC separation[Chiralpak AD-H (25×2.0 cm), 5 μM; mobile phase: Ethanol+0.1%isopropylamine 30%, flow rate: 46 mL/min, UV detection DAD 220 nm] toafford the two separated enantiomers 185 (t_(R)=11.0 min) and 186(t_(R)=12.5 min). Analytical data for the single enantiomers: whitesolid. UPLC/MS(ES⁺): m/z 571.36 [M+H]⁺.

Example 52 Preparation of Compound 187

Reaction of mesylate 4 with pyrrolidine followed by PMB-group removalaccording to Method C afforded 187 as a white solid (55% over 3 steps).UPLC/MS(ES⁺): m/z 574.20 [M+H]⁺.

Example 53 Preparation of Compound 188

Reaction of mesylate 4 with piperidine followed by PMB-group removalaccording to Method C afforded 188 as a white solid (6% over 3 steps).UPLC/MS(ES⁺): m/z 588.20 [M+H]⁺.

Example 54 Preparation of Compound 189

Reaction of epoxide 2 with cyclopropylamine followed by PMB-groupremoval according to Method D afforded 189 as a white solid (11% over 3steps). UPLC/MS(ES⁺): m/z 560.10 [M+H]⁺.

Example 55 Preparation of Compound 190

Reaction of epoxide 2 with 1-Boc-piperazine followed by PMB-groupremoval according to Method C afforded 190 (17% over 3 steps).UPLC/MS(ES⁺): m/z 589.30 [M+H]⁺.

Example 56 Preparation of Compound 191

Reaction of epoxide 2 with imidazole followed by PMB-group removalaccording to Method B afforded 191 as a white solid (12% over 3 steps).UPLC/MS(ES⁺): m/z 571.30 [M+H]⁺.

Example 57 Preparation of Compounds 192 and 193

Reaction of epoxide 2 with 1H-1,2,3-triazole followed by PMB-groupremoval according to Method B afforded compounds 192 (10% over 3 steps)and 193 (18% over 3 steps). 192: UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺. 193:UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺.

Example 58 Preparation of Compound 194

Reaction of epoxide 2 with 1H-1,2,4-triazole followed by PMB-groupremoval according to Method B afforded compound 194 (24% over 3 steps).UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺.

Example 59 Preparation of Compound 195

A mixture of epoxide 2 (80 mg, crude) and 7M NH₃-MeOH (1.5 mL) in MeOH(2 mL) was stirred at r.t. for 18 h. The volatiles were removed underreduced pressure. The resulting crude 195-1 was dissolved in DCM (1 mL)and treated with TEA (15 uL) and AcCl (11 uL). The mixture was stirredat r.t. for 1 h. The volatiles were removed under reduced pressure.Deprotection of the PMB-ether using TFA:DCM afforded 195 as a whitesolid (7% overall). UPLC/MS(ES⁺): m/z 562.30 [M+H]⁺.

Example 60 Preparation of Compound 196

n-BuLi (1.6M solution in hexanes, 650 μL, 1.04 mmol) was added to asuspension of tert-butyl 3-oxopiperazine-1-carboxylate (160 mg, 0.800mmol) in dry THF (2 mL), which had been pre-cooled to 0° C. The mixturewas stirred for 5 mins at 0° C. and then warmed to r.t. After 5 mins, asolution of epoxide 2 (200 mg, crude) in THF (1 mL) was added. Themixture was heated to 50° C. and stirred at 50° C. for 12 h. Water andEtOAc were added. The layers were separated, and the aqueous portion wasextracted with EtOA. The combined organic portions were dried withNa₂SO₄ and filtered. The volatiles were removed under reduced pressure.The crude 6 was dissolved in MeOH (5 mL) and treated with 6M aq. HClsolution (2 mL). The mixture was heated to 60° C. and stirred at 60° C.for 1.5 h. A majority of the volatiles were removed under reducedpressure. The residue was purified by reverse phase chromatography(water:CH₃CN 100:0 to 40:60) to afford 196 as a white solid (31 mg, 16%over 3 steps). UPLC/MS(ES⁺): m/z 603.30 [M+H]⁺.

Example 61 Preparation of Compound 197

Bromo(ethynyl)magnesium (4.90 mL, 2.46 mmol) was added to a solution of1 (300 mg, 0.493 mmol) in THF (15 mL), which had been warmed to 55° C.The mixture was stirred for 30 mins and quenched with sat. aq. NH₄Clsolution. The aqueous portion was extracted with EtOAc (2×). Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(DCM:EtOAc, 100:0 to 80:20) afforded 7 as a light yellow solid (130 mg,41%). UPLC/MS(ES+): m/z 635.20 [M+H]⁺.

A mixture of aq formaldehyde (37% solution, 630 uL, 0.780 mmol) andglacial AcOH (7 uL, 0.117 mmol) in THF (500 uL) was stirred at r.t. for15 mins. Sodium azide (7.6 mg, 0.117 mmol) and 7 (50.0 mg, 0.078 mmol)were sequentially added. After 10 mins, aq. sodium ascorbate (0.5 Msolution, 32 uL, 0.016 mmol) and CuSO₄ (1.2 mg, 0.008 mmol) were added.The mixture was stirred at r.t. for 18 h. The volatiles were removedunder reduced pressure. The residue was treated with a 3:1 MeOH:2N aqNaOH solution (4 mL), and the mixture was stirred at r.t. for 18 h. Thevolatiles were removed under reduced pressure, and the residue waspartitioned between EtOAc and water. The layers were separated, and theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure to afford crude 8 (34 mg), which was used in next stepwithout further purification. UPLC/MS(ES⁺): m/z 678.25 [M+H]⁺.

A solution of 8 (34 mg) in 10:1 DCM-TFA (5 mL) was stirred at r.t. for20 mins. The reaction was quenched with 2M aq. NaOH solution. The layerswere separated, and the organic portion was concentrated under reducedpressure. The residue was purified by reverse phase chromatography(water:CH₃CN, 95:5 to 0:100) to afford 197 as a white solid (5.5 mg, 13%over 2 steps). UPLC/MS(ES⁺): m/z 558.11 [M+H]⁺.

Example 62 Preparation of Compounds 198 and 199

Potassium carbonate (40.0 mg, 0.295 mmol) and MeI (20.0 mg, 0.141 mmol)were added to a solution of 8 (80.0 mg, 0.118 mmol) in CH₃CN (4 mL). Themixture was stirred at r.t. for 4 h, diluted with water and extractedwith EtOAc (3×). The combined organic portions were dried with Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography of theresidue (DCM:EtOAc, 70:30 to 0:100) afforded the two separatedregioisomers 9 (21 mg, 25%) and 10 (24 mg, 29%). 9: UPLC/MS(ES+): m/z692.29 [M+H]⁺. 10: UPLC/MS(ES+): m/z 692.28 [M+H]⁺.

General procedure for PMB-removal: A solution of PMB-ether (0.1 mmol) in10:1 DCM:TFA (3 mL) was stirred at r.t. for 30 mins. The reaction wasquenched with 2M aq. NaOH solution. The layers were separated, and theorganic portion was concentrated under reduced pressure. Chromatographyof the residue (EtOAc:MeOH, 100:0 to 90:10) afforded the product. 198.(derived from 9) UPLC/MS(ES⁺): m/z 572.38 [M+H]⁺. 199: (derived from 10)UPLC/MS(ES⁺): m/z 572.43 [M+H]⁺.

Example 63 Preparation of Compounds 200, 201, 202, 203 and 204

Sodium hydride (1.80 g, 44.7 mmol) was added to a stirred solution of2-1 (11.6 g, 40.7 mmol) in dry DMF (75 mL), which had been pre-cooled to0° C. The mixture was stirred at 0° C. for 10 mins, and then warmed tor.t. The mixture was then stirred for 30 mins. The reaction was cooledto 0° C. and 3-bromo-2-methylprop-1-ene (5.70 g, 42.7 mmol) was addeddropwise. The mixture was allowed to gradually reach r.t., and stirringwas continued for 20 h. EtOAc and sat. aq. NH₄Cl solution were added.The layers were separated, and the organic portion was washed withbrine, dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to50:50) afforded 2-2 (12.1 g, 87%). UPLC/MS(ES⁺): m/z 339.80 [M+H]⁺.

A mixture of 2-2 (12.0 g, 35.4 mmol), sodium formate (2.70 g, 40.7mmol), tetrabutylammonium chloride (9.80 g, 35.4 mmol), Pd(OAc)₂ (396mg, 1.7 mmol) and TEA (14.7 mL, 106 mmol) in dry DMF (300 mL) wasdegassed and heated to 100° C. for 3 h. EtOAc and sat. aq. NH₄Clsolution were added. The layers were separated, and the organic portionwas washed with brine, dried with Na₂SO₄, filtered and concentratedunder reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 2-3 as a pale yellow wax(6.15 g, 81%). UPLC/MS(ES⁺): m/z 213.91 [M+H]⁺.

A mixture of 2-3 (1.80 g, 8.45 mmol), (3-chloro-4-fluorophenyl)boronicacid (2.94 g, 16.9 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (618 mg,0.84 mmol) and aq. Na₂CO₃ (2M solution, 8.45 mL, 16.9 mmol) in DCE (80mL) was degassed and heated to 100° C. under microwave irradiation.Water and DCM were added. The layers were separated, and the organicphase was dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to50:50) afforded 2-4 as a white solid (1.97 g, 76%). UPLC/MS(ES⁺): m/z307.18 [M+H]⁺.

Dess-Martin periodinane (6.8 g, 16.0 mmol) was added to a stirredsolution of 2-4 (1.97 g, 6.40 mmol) in dry DCM (28 mL). The mixture wasstirred at r.t. under N₂ atmosphere for 1 h. The reaction was quenchedwith a 1:1 2M aq. Na₂S₂O₃:sat. aq. NaHCO₃ solution (30 mL), the mixturewas vigorously stirred for 30 mins. The layers were separated, and theorganic portion was washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc 100:0 to 70:30) afforded 2-5 as a white solid (1.40g, 72%). UPLC/MS(ES⁺): m/z 306.15 [M+H]⁺.

TMSCF₃ (810 uL, 5.50 mmol) was added to a solution of 2-5 (1.40 g, 4.60mmol) in dry DCM (25 mL). The mixture was cooled 0° C. and TBAF (1M solin THF, 5.5 mL, 5.50 mmol) was added dropwise. The mixture was allowedto gradually reach r.t. and stirring was continued for 1 h. Water andDCM were added. The layers were separated, and the organic portion wasdried with Na₂SO₄ and filtered. The volatiles were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to80:20) afforded 2-6 (1.43 g, 82%). UPLC/MS(ES⁺): m/z 376.16 [M+H]⁺.

Dess-Martin periodinane (3.25 g, 7.68 mmol) was added to a stirredsolution of 2-6 (1.43 g, 3.84 mmol) in dry DCM (17 mL). The mixture wasstirred at r.t. for 1 h. A 1:1 2M aq. Na₂S₂O₃:sat. aq. NaHCO₃ solutionwas added. The mixture was stirred at r.t. for 30 mins. The layers wereseparated, and the aqueous portion was extracted with DCM (2×). Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc 100:0 to 70:30) afforded 2-7 as a white solid (1.20g, 84%). UPLC/MS(ES⁺): m/z 392.16 [M+H₃O]⁺

Trimethylsulfoxonium iodide (695 mg, 3.16 mmol) was added to a solutionof potassium tert-butoxide (354 mg, 3.16 mmol) in DMSO (6 mL). Themixture was stirred at r.t. for 30 mins. A solution of 2-7 (1.18 g, 3.16mmol) in DMSO (20 mL) was added, and the mixture was stirred at r.t. for30 mins. EtOAc and water were added, and the layers were separated. Theaqueous portion was extracted with EtOAc. The combined organic extractswere washed with brine, dried with Na₂SO₄ and filtered. The volatileswere removed under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc 100:0 to 70:30) afforded 2-8 as a colourless wax (530mg, 43%). UPLC/MS(ES⁺): m/z 388.18 [M+H]⁺.

A solution of 2-8 (530 mg, 1.37 mmol) in 7M NH₃-MeOH (50 mL) was stirredat 45° C. for 1 h. The volatiles were removed under reduced pressure.The crude was purified by reverse phase chromatography (water:CH₃CN 95:5to 0:100) to afford 2-9 as a white solid (498 mg, 90%). UPLC/MS(ES⁺):m/z 405.21 [M+H]⁺.

Racemate 2-9 was resolved by using a prep-HPLC separation [ChiralpakAD-H (25×3 cm, 5 um), mobile phase: n-Hexane/(EtOH/MeOH+0.1% ipa) 96/4%v/v, flow rate: 32 mL/min, UV detection DAD 220 nm] to obtain the twoseparated enantiomers 2-9a (t_(R)=10.9 min) and 2-9b (t_(R)=14.5 min).UPLC and ¹H NMR analyses for the two enantiomers were superimposable.

General amide coupling conditions-Method A: A mixture of 2-9 (50.0 mg,0.124 mmol), EDC (31.0 mg, 0.161 mmol), HOBT (22.0 mg, 0.161 mmol) andacid (0.124 mmol) in DCM:DMF (5:1, 6 mL) was stirred at 45° C. for 2 h.DCM was added. The organic portion was washed with sat. aq. NH₄Clsolution and brine, dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue afforded the product.

General amide coupling conditions-Method B: DIPEA (281 uL, 1.62 mmol)was added to a solution of acid (1.06 mmol) and HATU (461 mg, 1.21 mmol)in dry DMF (5 mL). After 20 mins, a solution of 2-9 (330 mg, 0.81 mmol)in DMF (5 mL) was added. The mixture was stirred at r.t. until complete.EtOAc and sat. aq. NH₄Cl solution were added. The layers were separated,and the aqueous portion was extracted with EtOAc. The combined organicportions were dried with Na₂SO₄ and filtered. The volatiles were removedunder reduced pressure. Chromatography of the residue afforded theproduct.

Coupling of 2-9 with acid 2-10 according to Method A afforded 200 as awhite solid (30%, mixture of 4 isomers). UPLC/MS(ES+): m/z 638.18[M+H]⁺. Racemate 200 was resolved by using a prep-HPLC separation[Chiralpak AD-H (25×2 cm, 5 um), mobile phase: Ethanol+0.1%isopropylamine 20% v/v, flow rate: 45 mL/min, UV detection DAD 220 nm]to obtain the four separated isomers 201 (t_(R)=12.9 min), 203(t_(R)=14.8 min), 202 (t_(R)=16.6 min) and 204 (t_(R)=23.6 min).

Alternatively, 2-9a and 2-9b were separately coupled with 2-10 accordingto Method B. Each diastereomeric mixture was resolved by chiral HPLC.2-9a provided a mixture of 204 (t_(R)=6.5 min) and 202 (t_(R)=14.1 min)[Whelk 01 (R,R) (25×2.0 cm), 5μ, mobile phase: n-Hexane/(Ethanol+0.1%isopropylamine) 30/70% v/v, flow rate: 17 mL/min, UV detection DAD 220nm], 2-9b provided a mixture of 201 and 203 (t_(R) 6.4 min and 12.3 min)[Whelk O1 (R,R) (25×2.0 cm), 5μ, mobile phase: n-Hexane/(Ethanol+0.1%isopropylamine) 30/70% v/v, flow rate: 17 mL/min, UV detection DAD 220nm].

Example 64 Preparation of 2-10

Compound 2-12 (4.86 g, 26.7 mmol) was added to a stirring suspension ofcesium carbonate (15.4 g, 47.5 mmol) in DCM (120 mL). A solution of 2-11(3.13 g, 19.0 mmol) in DCM (20 mL) was added. The mixture was stirred atr.t. for 5 h. The mixture was filtered through a pad of Celite, washedthoroughly with DCM and concentrated. The residue was dissolved inEtOAc. The organic portion was washed with water and brine, dried withNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof the residue (cyclohexane:EtOAc 100:0 to 0:100) afforded 2-13 as awhite solid (4.50 g, 89%). UPLC/MS(ES⁺): m/z 266.15 [M+H]⁺.

Lithium hydroxide monohydrate (258 mg, 6.10 mmol) was added to asuspension of 2-13 (1.50 g, 5.60 mmol) in a 1:1:6 THF:MeOH:H₂O mixture(40 mL). The mixture was stirred at r.t. for 3 h, loaded on a reversephase cartridge and eluted with water to afford 2-10 as a white solid(1.10 g, 78%). UPLC/MS(ES⁺): m/z 252.13 [M+H]⁺.

Example 65 Preparation of Compounds 205 and 206

Coupling of 2-9a with 3,4-dimethoxybenzoic acid according to Method Aafforded 205 as a white solid (51%). UPLC/MS(ES⁺): m/z 569.40 [M+H]⁺.Using 2-9b and 3,4-dimethoxybenzoic acid according to Method A afforded206 as a white solid (50%). UPLC/MS(ES⁺): m/z 569.40 [M+H]⁺.

Example 66 Preparation of Compounds 207

Coupling of 2-9 with 2-14 according to Method A afforded 207 as a whitesolid (43%). UPLC/MS(ES⁺): m/z 576.32 [M+H]⁺.

Example 67 Preparation of 2-14

Acrolein (21.8 mL, 326 mmol) was added to a mixture of4-amino-3-hydroxybenzoic acid (5.00 g, 33.0 mmol) in 12 N aq. HClsolution (50 mL). The mixture was refluxed for 1 h. After cooling tor.t., the mixture was concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (water:CH₃CN 100:0 to50:50) to afford 2-14 (561 mg, 9%). UPLC/MS(ES⁺): m/z 190.04 [M+H]⁺.

Example 68 Preparation of Compound 208

Coupling of 2-9 with 2-15 according to Method A afforded 208 as a whitesolid (67%). UPLC/MS(ES⁺): m/z 590.25 [M+H]⁺.

Example 69 Preparation of 2-15

Cesium carbonate (2.58 g, 7.92 mmol) and MeI (822 uL, 13.2 mmol) weresequentially added to a solution of 2-14 (500 mg, 2.64 mmol) in DMF (30mL). The mixture was stirred at r.t. for 18 h. EtOAc was added. Theorganic portion was washed with 2M aq. HCl solution and water, driedwith Na₂SO₄, filtered and concentrated under reduced pressure. Crude2-16 was dissolved in a 2:1:1 THF:MeOH:H₂O mixture (8 mL). Lithiumhydroxide monohydrate (332 mg, 7.92 mmol) was added, and the mixture wasstirred at r.t. for 1 h. The volatiles were removed under reducedpressure. The residue was dissolved in water, and the pH of the solutionwas adjusted to 6 with 1M aq. HCl solution. The aqueous portion wasextracted with DCM (2×). The combined organic portions were dried withNa₂SO₄, filtered and concentrated under reduced pressure to afford crude2-15 (227 mg), which was used in the next step without furtherpurification. UPLC/MS(ES⁺): m/z 204.10 [M+H]⁺.

Example 70 Preparation of Compound 209

Coupling of 2-9 with 4-cyclopropoxy-3-methoxybenzoic acid according toMethod A afforded 209 as a white solid (41%). UPLC/MS(ES⁺): m/z 595.30[M+H]⁺.

Example 71 Preparation of Compound 210

Coupling of 2-9 with 4-(carbamoylmethoxy)-3-methoxybenzoic acidaccording to Method B afforded 210 as a white solid (51%). UPLC/MS(ES⁺):m/z: 612.21 [M+H]⁺.

Example 72 Preparation of Compound 211

Coupling of 2-9 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acidaccording to Method B afforded 211 as a white solid (45%). UPLC/MS(ES⁺):m/z 613.27 [M+H]⁺.

Example 73 Preparation of Compound 212

Coupling of 2-9 with 2-17 according to Method B afforded 212 as a whitesolid (33%). UPLC/MS(ES⁺): m/z 636.00 [M+H]⁺.

Example 74 Preparation of 2-17

LDA (2M solution in THF, 1.05 mL, 2.10 mmol) was added to a stirredsolution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (276 uL, 1.62 mmol)in THF (1 mL), which had been pre-cooled to −78° C. After 15 mins, asolution of methyl 4-(bromomethyl)-3-methoxybenzoate (460 mg, 1.78 mmol)in THF (1 mL) was added dropwise to the mixture and stirring at 78° C.was continued for 1 h. The reaction was quenched with water. The aqueousportion was extracted with EtOAc (2×). The combined organic portionswere dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc 70:30)afforded 2-18 (199 mg, 34%). UPLC/MS(ES⁺): m/z 364.20 [M+H]⁺.

A solution of 2-18 (199 mg, 0.547 mmol) in 5:1 DCM:TFA (3 mL) wasstirred at r.t. for 5 mins. The mixture was diluted with DCM. Theorganic portion was washed with a sat. aq. NaHCO₃ solution, dried withNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (0.1% HCOOH:water:0.1%HCOOH:CH₃CN 100:0 to 0:100) to afford 2-19.

Compound 2-19 was dissolved in a 2:1:1 THF:MeOH:H₂O mixture (10 mL).Lithium hydroxide monohydrate (45 mg, 1.10 mmol) was added. The mixturewas stirred at r.t. for 2 h. The volatiles were removed under reducedpressure to afford crude 2-17, which was directly used in the next stepwithout further purification. UPLC/MS(ES⁺): m/z 250.20 [M+H]⁺.

Example 75 Preparation of Compound 213

Coupling of 2-9 with 2-20 according to Method B afforded 213 as a whitesolid (73%). UPLC/MS(ES⁺): m/z 604.00 [M+H]⁺.

Example 76 Preparation of 2-20

Crotonaldehyde (4.01 g, 48.9 mmol) was added dropwise to a mixture of4-amino-3-hydroxybenzoic acid (5.00 g, 33.1 mmol) and 6M aq. HClsolution (60 mL, 360 mmol). The mixture was refluxed for 18 h. Aftercooling to r.t. a precipitate formed. The solid was filtered off, driedand collected. Acid 2-21 (3.44 g) was used in the next step withoutfurther purification. UPLC/MS(ES⁺): m/z 204.10 [M+H]⁺.

Cesium carbonate (15.8 g, 48.6 mmol) and MeI (5.88 mL, 94.5 mmol) weresequentially added to a solution of 2-21 (3.04 g) in DMF (80 mL). Themixture was stirred at r.t. for 12 h. DMF was removed under reducedpressure, and the residue was taken up with EtOAc. The organic portionwas washed with water, dried with Na₂SO₄, filtered and concentratedunder reduced pressure to afford crude 2-22 (2.76 g), which was used inthe next step without further purification. UPLC/MS(ES⁺): m/z 232.10[M+H]⁺.

Lithium hydroxide monohydrate (0.272 g, 6.49 mmol) was added to astirred suspension of 2-22 (500 mg, 2.16 mmol) in a 2:1:2 THF:MeOH:H₂Omixture. The mixture was stirred at r.t. for 3 h. The volatiles wereremoved under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-20 (291mg). UPLC/MS(ES⁺): m/z 218.10 [M+H]⁺.

Example 77 Preparation of Compound 214

Coupling of 2-9 with 2-23 according to Method B afforded 214 as a whitesolid (49%). UPLC/MS(ES⁺): m/z 633.26 [M+H]⁺.

Example 78 Preparation of 2-23

Ester 2-22 (1.50 g, 6.48 mmol) was added to a suspension of seleniumdioxide (1.44 g, 13.0 mmol) in pyridine (24 mL). The mixture wasrefluxed for 3 h. The volatiles were removed under reduced pressure, andthe residue was triturated with EtOAc. The solid was dried and collectedto provide 2-24 (595 mg, 35%). UPLC/MS(ES⁺): m/z 262.10 [M+H]⁺.

Oxalyl chloride (100 uL, 1.14 mmol) and DMF (1 drop) were added to asolution of 2-24 (230 mg, 0.880 mmol) in DCM (7 mL). The mixture wasstirred at r.t. for 30 mins. HMDS (400 uL, 1.89 mmol) and then MeOH wereadded. The mixture was concentrated under reduced pressure.Chromatography of the residue (EtOAc-DCM, 100:0 to 0:100) afforded 2-25.UPLC/MS(ES⁺): m/z 261.10 [M+H]⁺.

Lithium hydroxide monohydrate (44.0 mg, 1.05 mmol) was added to astirred suspension of 2-25 (91.0 mg, 0.350 mmol) in a 2:1:2 THF:MeOH:H₂Omixture. The mixture was stirred at r.t. for 2 h. The volatiles wereremoved under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-23 (76 mg,89%). UPLC/MS(ES⁺): m/z 247.20 [M+H]⁺.

Example 79 Preparation of Compound 215

Coupling of 2-9 with 2-26 according to Method B afforded 215 as a whitesolid (41%). UPLC/MS(ES⁺): m/z 615.26 [M+H]⁺.

Example 80 Preparation of 2-26

SOCl₂ (420 uL, 5.76 mmol) and TEA (800 uL, 5.76 mmol) were added to asolution of 2-25 (150 mg, 0.576 mmol) in DCE (10 mL), which had beenpre-cooled to 0° C. The mixture was stirred at 0° C. for 3 h. Thereaction was quenched with a sat. aq. NaHCO₃ solution. The layers wereseparated, and the aqueous portion was extracted with EtOAc. Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-27 (100mg, 71%). UPLC/MS(ES⁺): m/z 243.18 [M+H]⁺.

Lithium hydroxide monohydrate (21.0 mg, 0.49 mmol) was added to astirred suspension of 2-27 (100 mg, 0.413 mmol) in a 2:2:1 THF:MeOH:H₂Omixture (10 mL). The mixture was stirred at r.t. for 2 h. The volatileswere removed under reduced pressure. Crude 2-26 was used in the nextstep without further purification. UPLC/MS(ES⁺): m/z 229.14 [M+H]⁺.

Example 81 Preparation of Compound 216

Coupling of 2-9 with 2-28 according to Method B afforded 216 as a whitesolid (46%). UPLC/MS(ES⁺): m/z 637.30 [M+H]⁺.

Example 82 Preparation of 2-28

NaH (153 mg, 3.83 mmol) was added to a solution of imidazolidin-2-one(300 mg, 3.48 mmol) in THF (3 mL), which had been pre-cooled to 0° C.After 1 h, methyl 4-(bromomethyl)-3-methoxybenzoate (899 mg, 3.48 mmol)was added. The mixture was stirred at r.t. for 18 h, poured in to waterand extracted with EtOAc (3×). The combined organic portions were driedwith Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue (EtOAc:MeOH 100:0 to 80:20) afforded 2-29as a white solid (40 mg, 4%). UPLC/MS(ES⁺): m/z 265.20 [M+H]⁺.

Lithium hydroxide monohydrate (19.0 mg, 0.454 mmol) was added to astirred suspension of 2-29 (40.0 mg, 0.151 mmol) in a 2:2:1 THF:MeOH:H₂Omixture (8 mL). The mixture was stirred at r.t. for 18 h. The volatileswere removed under reduced pressure. The residue was taken up withwater, and the aqueous portion was extracted with EtOAc (2×). Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(EtOAc:MeOH 100:0 to 80:20) afforded 2-28 as a white solid (32 mg, 84%).UPLC/MS(ES⁺): m/z 251.20 [M+H]⁺.

Example 83 Preparation of Compound 217

Triethylamine (0.240 mL, 1.72 mmol) was added to a mixture of3-methoxy-4-[(2-oxopyrrolidin-3-yl)oxy]benzoic acid (130 mg, 0.517mmol), HOBT (87.3 mg, 0.646 mmol), EDC (124 mg, 0.646 mmol) and 2-30(104 mg, 0.431 mmol) in a 4:1 DCM:DMF (5 mL). The mixture was warmed to45° C. and stirred at 45° C. for 18 h. A 1M aq. HCl solution was added,and the mixture was stirred at r.t. for 10 mins. The layers wereseparated. The organic portion was washed with 1M aq. HCl solution,dried with Na₂SO₄, filtered and concentrated under reduced pressure toafford crude 2-31 (203 mg), which was used in the next step withoutfurther purification. UPLC/MS(ES⁺): m/z 476.30 [M+H]⁺.

Dess-Martin periodinane (453 mg, 1.07 mmol) was added to a stirredsolution of 2-31 (203 mg) in dry DCM (10 mL). The mixture was stirred atr.t. for 2 h, and the reaction was quenched with a 1:1 1M aq.Na₂S₂O₃:sat. aq. NaHCO₃ solution (3 mL). The mixture was stirredvigorously for 30 mins. The layers were separated, and the organicportion was washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(EtOAc:MeOH, 100:0 to 75:25) afforded 2-32 (80 mg, 39% over two steps).UPLC/MS(ES⁺): m/z 474.30 [M+H]⁺.

A mixture of 2-32 (10.0 mg, 0.021 mmol),(3-chloro-4-fluorophenyl)boronic acid (18.4 mg, 0.105 mmol), Pd(dppf)Cl₂(2.0 mg, 0.003 mmol) and aq. Na₂CO₃ (2M solution, 0.105 mmol, 0.05 mL)in DCE (0.3 mL) was degassed and stirred while heated to 85° C. undermicrowave irradiation (4 cycles for 10 mins each). After each run, afurther aliquot of Pd(dppf)Cl₂ (2.0 mg, 0.003 mmol) was added. Thereaction was diluted with water, and DCM were added. The layers wereseparated, and the organic portion was concentrated under reducedpressure. The residue was purified by reverse phase chromatography(water:CH₃CN 100:0 to 0:100) to afford 217. UPLC/MS(ES⁺): m/z 568.30[M+H]⁺.

Example 84 Preparation of Compound 218

Trimethylsulfoxonium iodide (21.0 mg, 0.097 mmol) was added to asolution of potassium tert-butoxide (9.8 mg, 0.086 mmol) in DMSO (0.6mL). The mixture was stirred at r.t. for 30 mins. A solution of 218-1(50.0 mg, 0.088 mmol) in DMSO (0.6 mL) was added, and the mixture wasstirred at r.t. for a further 30 mins. The mixture was diluted withEtOAc and water. The layers were separated, and the aqueous portion wasextracted with EtOAc. The combined organic portions were washed withbrine, dried with Na₂SO₄, filtered and concentrated under reducedpressure to afford crude 2-33 (50 mg), which was used next step withoutfurther purification. UPLC/MS(ES⁺): m/z 582.34 [M+H]⁺.

A mixture of 2-33 (50 mg), potassium carbonate (24.0 mg, 0.170 mmol) andpyrazole (24.0 mg, 0.350 mmol) in DMF (1 mL) was stirred at 40° C. for18 h. The mixture was diluted with EtOAc and water. The layers wereseparated, and the aqueous portion was extracted with EtOAc. Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 50:50) to afford 218 as awhite solid (10 mg, 17% over two steps). UPLC/MS(ES⁺): m/z 650.40[M+H]⁺.

Example 85 Preparation of Compound 219

Epoxide 2-33 (60 mg, crude) was dissolved in a 1:1 3M aq. HCl sol:MeOHmixture (5 mL). The mixture was heated to 50° C. for 3 h. After coolingto r.t., the mixture was basified with 1M aq. NaOH solution andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 95:5 to 0:100) to afford 219 as awhite solid (18 mg, 26% over two steps). UPLC/MS(ES⁺): m/z 600.36[M+H]⁺.

Example 86 Preparation of Compound 220

Triethylamine (0.35 mL, 2.51 mmol) was added to a mixture of8-methoxyquinoline-6-carboxylic acid (286 mg, 1.18 mmol), HOBT (223 mg,1.65 mmol), EDC (316 mg, 1.65 mmol) and 2-30 (239 mg, 1.18 mmol) in DCM(7 mL). The mixture was stirred at r.t. for 60 h. A 1M aq. HCl solutionwas added, and the mixture was stirred at r.t. for 10 mins. The layerswere separated. The organic portion was washed with 1M aq. HCl solution,dried with Na₂SO₄, filtered and concentrated under reduced pressure toafford crude 2-34, which was used in the next step without furtherpurification. UPLC/MS(ES⁺): m/z 428.30 [M+H]⁺.

Dess-Martin periodinane (1.20 g, 2.82 mmol) was added to a stirredsolution of 2-34 in dry DCM (6 mL). The mixture was stirred at r.t. for2 h, and the reaction quenched with a 1:1 1M aq. Na₂S₂O₃:sat. aq. NaHCO₃solution. The mixture was stirred vigorously for 30 mins. The layerswere separated, and the organic portion was washed with brine, driedwith Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography (water:CH₃CN 80:20to 0:100) to afford 2-35 (11.0 mg, 2% overall). UPLC/MS(ES⁺): m/z 426.20[M+H]⁺.

A mixture of 2-35 (11.0 mg, 0.026 mmol),(3-chloro-4-fluorophenyl)boronic acid (11.2 mg, 0.065 mmol), Pd(dppf)Cl₂(1.3 mg, 0.002 mmol) and aq. Na₂CO₃ (2M solution, 39 uL, 0.078 mmol) inDCE (1 mL) was degassed and heated to 85° C. for 24 h. The volatileswere removed under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 30:70) to afford 220 as anoff-white solid (2.3 mg, 17%). UPLC/MS(ES⁺): m/z 520.30 [M+H]⁺.

Example 87 Preparation of Compound 221

Trimethylsulfoxonium iodide (18.3 mg, 0.087 mmol) was added to asolution of potassium tert-butoxide (9.3 mg, 0.083 mmol) in DMSO (0.3mL). The mixture was stirred at r.t. for 30 mins. A solution of 220(43.0 mg, 0.083 mmol) in DMSO (0.7 mL) was added, and the mixture wasstirred at r.t. for a further 30 mins. The mixture was partitionedbetween EtOAc and water. The layers were separated, and the aqueousportion was extracted with EtOAc. The combined organic portions werewashed with brine, dried with Na₂SO₄, filtered and concentrated underreduced pressure. The residue was dissolved in a 1:1 3M aq. HCl sol:MeOHmixture (3 mL), and the mixture was heated to 50° C. for 3 h. Thevolatiles were removed under reduced pressure. The residue was purifiedby reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford221 as an off-white solid. UPLC/MS(ES⁺): m/z 552.38 [M+H]⁺.

Example 88 Preparation of Compound 222

NaH (59.0 mg, 1.47 mmol) was added to a solution of 2-13 (300 mg, 1.13mmol) in dry THF (4.5 mL). After 5 mins of stirring at r.t., MeI (192mg, 1.35 mmol) was added. The reaction was stirred at r.t. for 3 h.EtOAc and 1M aq. HCl solution were added. The layers were separated, andthe aqueous portion was extracted with EtOAc. The combined organicportions were dried with Na₂SO₄ and filtered. The volatiles were removedunder reduced pressure to afford crude 2-36, which was in the next stepwithout further purification. Lithium hydroxide monohydrate (95.0 mg,2.26 mmol) was added to a stirred mixture of 2-36 in 2:1:1 THF:MeOH:H₂O(8 mL). The reaction was stirred at r.t. for 3 h. Additional lithiumhydroxide monohydrate (95 mg) was added and stirring was continued for 2h. The mixture was poured in to 6M aq. HCl solution. The aqueous portionwas saturated with NaCl and extracted with EtOAc and DCM. The combinedorganic portions were dried with Na₂SO₄, and filtered. The volatileswere removed under reduced pressure to afford crude 2-37, which was inthe next step without further purification. UPLC/MS(ES⁺): m/z 266.20[M+H]⁺.

A mixture of 2-37, 2-30 (273 mg, 1.13 mmol), EDC (282 mg, 1.47 mmol),HOBT (198 mg, 1.47 mmol) and TEA (267 uL, 1.92 mmol) in DMF (8 mL) wasstirred at r.t. for 18 h. EtOAc and 2M aq. HCl solution were added. Thelayers were separated, and the organic portion was concentrated underreduced pressure. The residue was purified by reverse phasechromatography (water:CH₃CN 100:0 to 0:100) to afford 2-38 as acolorless wax (90 mg, 16% over 3 steps). UPLC/MS(ES⁺): m/z 490.30[M+H]⁺.

Dess-Martin periodinane (195 mg, 0.46 mmol) was added to a stirredsolution of 2-38 (90.0 mg, 0.184 mmol) in dry DCM (2 mL). The mixturewas stirred at r.t. for 2 h. The reaction was quenched with a 1:1 1M aq.Na₂S₂O₃:sat. aq. NaHCO₃ solution. The mixture was stirred vigorously for30 mins. The layers were separated, and the organic portion was washedwith brine, dried with Na₂SO₄, filtered and concentrated under reducedpressure to afford crude 2-39 (92 mg), which was in the next stepwithout further purification. UPLC/MS(ES⁺): m/z 488.30 [M+H]⁺.

A mixture of 2-39 (92 mg), (3-chloro-4-fluorophenyl)boronic acid (83.0mg, 0.475 mmol), Pd(dppf)Cl₂ (27.6 mg, 0.038 mmol) and aq. Na₂CO₃ (2Msolution, 285 uL, 0.570 mmol) in DCE (3 mL) was degassed and heated to100° C. under microwave irradiation for 1.5 h. Water and DCM were added.The layers were separated, and the organic portion was dried withNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (water:CH₃CN 100:0 to0:100) to afford 222 as an off-white solid (27.0 mg, 25% over twosteps). UPLC/MS(ES⁺): m/z 582.30 [M+H]⁺.

Example 89 Preparation of Compound 223

2-Methyl-2-butene (16.9 mL, 33.7 mmol, 2M solution in THF) was added toa solution of 2-5 (1.03 g, 3.37 mmol) in tert-butanol (60 mL). Asolution of sodium chlorite (609 mg, 6.74 mmol) and sodium phosphatemonobasic dihydrate (3.41 g, 21.9 mmol) in water (60 mL) was then added.The mixture was stirred at r.t. for 18 h. Brine was added, and theaqueous portion was extracted with EtOAc (3×). The combined organicportions were dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to0:100) afforded 2-40 as an off-white solid (688 mg, 63%). UPLC/MS(ES⁺):m/z 322.10 [M+H]⁺.

Triethylamine (0.160 mL, 1.12 mmol) was added to a mixture of 2-40 (200mg, 0.622 mmol), HOBT (151 mg, 1.12 mmol), EDC (167 g, 0.870 mmol) andNO-dimethylhydroxylamine hydrochloride (91.1 mg, 0.934 mmol) in DCM (15mL). The mixture was stirred at r.t. for 18 h. A 1M aq. HCl solution wasadded, and the mixture was stirred at r.t. for 10 mins. The layers wereseparated. The organic portion was washed with 1M aq. HCl solution,dried with Na₂SO₄, filtered and concentrated under reduced pressure toafford crude 2-41 (255 mg) which was used in the next step withoutfurther purification. UPLC/MS(ES⁺): m/z found 365.20 [M+H]⁺.

Cyclopropylmagnesium bromide (1M solution in 2-methyl tetrahydrofuran,1.96 mL, 1.96 mmol) was added to a solution of 2-41 (255 mg) in THF (10mL). The mixture was stirred at r.t. for 1 h. The reaction was quenchedwith sat. aq. NH₄Cl solution and extracted with DCM (3×). The combinedorganic portions were dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane-EtOAc,100:0 to 50:50) afforded 2-42 (146 mg, 68% over 2 steps). UPLC/MS(ES⁺):m/z: 346.20 [M+H]⁺.

A mixture of trimethylsulfoxonium iodide (93.0 mg, 0.423 mmol) and NaH(16.9 mg, 0.423 mmol) in 1:1 DMSO:THF (1 mL) was stirred at r.t. for 1h. A solution of 2-42 (146 mg, 0.423 mmol) in THF (1 mL) was added, andthe mixture was stirred at r.t. for 18 h. The mixture was partitionedbetween EtOAc and water. The layers were separated, and the aqueousportion was extracted with EtOAc. The combined organic portions weredried with Na₂SO₄, filtered and concentrated under reduced pressure toafford crude 2-43 (180 mg), which was used in the next step withoutfurther purification.

A solution of 2-43 (180 mg) in 7M NH₃:MeOH (4 mL) was stirred at r.t.for 18 h and at 35° C. for an addition 24 h. The volatiles were removedunder reduced pressure. The residue was purified by reverse phasechromatography (water:CH₃CN 100:0 to 0:100) to afford 2-44 (13 mg, 8%over 2 steps). UPLC/MS(ES⁺): m/z 377.20 [M+H]⁺.

A mixture of 2-10 (39.9 mg 0.159 mmol), HOBT (25.8 mg, 0.191 mmol), EDC(28.4 mg, 0.148 mmol), TEA (0.027 mL, 0.191 mmol) and 2-44 (40.0 mg,0.106 mmol) in DMF (2 mL) was stirred at r.t. for 18 h. A 1M aq. HClsolution was added, and the mixture was stirred at r.t. for 10 mins. Thelayers were separated. The organic portion was washed with 1M aq. HClsolution, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by reverse phase chromatography(water:CH₃CN 100:0 to 0:100) to afford 223 (8 mg, 12%). UPLC/MS(ES⁺):m/z 610.50 [M+H]⁺.

Example 90 Preparation of Compound 224

Coupling of 2-44 with 2-14 using conditions reported for the preparationof 223 (EDC, HOBT) afforded 224 as a white solid. UPLC/MS(ES⁺): m/z562.40 [M+H]⁺.

Example 91 Preparation of Compound 225

Trimethylsulfoxonium iodide (21.5 mg, 0.098 mmol) was added to a mixtureof potassium tert-butoxide (9.98 mg, 0.089 mmol) in DMSO (2 mL). After30 mins, 2-45 (57.8 mg, 0.089 mmol) was added, and the mixture wasstirred at r.t. for 1.5 h. The mixture was partitioned between EtOAc andwater. The layers were separated, and the aqueous portion was extractedwith EtOAc. The combined organic portions were dried with Na₂SO₄,filtered and concentrated under reduced pressure to afford crude 2-46,which was used in the next step without purification. Crude 2-46 wasdissolved in DMF (1 mL). K₂CO₃ (24.6 mg, 0.178 mmol) and imidazole (12.1mg, 0,178 mmol) were then sequentially added. The mixture was heated to80° C. and stirred at 80° C. for 48 h. The volatiles were removed underreduced pressure to afford crude 2-47, which was used in the next stepwithout purification.

A solution of 2-47 in 1:1 TFA:DCM (0.9 mL) was stirred at r.t. for 1 h.The reaction was quenched with a 1M aq. NaOH solution. After 30 mins ofstirring at r.t., the layers were separated. The organic portion wasdried with Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography to afford 225 as awhite solid (1 mg, 2% overall). UPLC/MS(ES⁺): m/z 611.30 [M+H]⁺.

Example 92 Preparation of Compound 226

NaH (9.0 mg, 0.226 mmol) was added to a solution of trimethylsulfoxoniumiodide (49.7 mg, 0.226 mmol) in DMSO (2 mL). After 40 mins a solution of220 (117 mg, 0.226 mmol) in THF (2 mL) was added, and the mixture wasstirred at r.t. for 6 h. The mixture was partitioned between water andEtOAc. The layers were separated, and the aqueous portion was extractedwith EtOAc. The combined organic portions were dried with Na₂SO₄,filtered and concentrated under reduced pressure to afford crude 2-48,which was used in the next step without purification. UPLC/MS(ES⁺): m/z534.30 [M+H]⁺.

Potassium carbonate (31.3 mg, 0.452 mmol) and imidazole (30.8 mg, 0.452mmol) were sequentially added to a solution of 2-48 in DMF (2 mL). Themixture was heated to 120° C. for 18 h. The volatiles were removed underreduced pressure. The residue was purified by reverse phasechromatography (water:CH₃CN 100:0 to 0:100) to afford 226 as a whitesolid (10 mg, 7% over 2 steps). UPLC/MS(ES⁺): m/z 602.50 [M+H]⁺.

Example 93 Preparation of Compound 227

A mixture of 2-49 (110 mg, 0.0 mmol), HOBT (86.0 mg, 0.640 mmol), EDC(122 mg, 0.640 mmol), TEA (120 uL, 0.860 mmol) and4-(2-fluoroethoxy)-3-methoxybenzoic acid (110 mg, 0.510 mmol) in DCM (4mL) was stirred at r.t. for 3 h. The reaction was quenched with 1M aq.HCl solution, and the mixture was stirred at r.t. for 10 mins. Thelayers were separated, and the organic portion was washed with 1M aq.HCl solution, dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc 60:40 to10:90) afforded 2-50 as a white solid (95 mg, 48%). UPLC/MS(ES⁺): m/z453.09 [M+H]⁺.

A mixture of 2-50 (45.0 mg, 0.100 mmol),(3-chloro-4-fluorophenyl)boronic acid (87.0 mg, 0.500 mmol), Pd(dppf)Cl₂(3.6 mg, 0.005 mmol) and aq. Na₂CO₃ (2M solution, 250 uL, 0.500 mmol) inDCE (1 mL) was degassed and stirred with heating to 85° C. for 3 h.Water and DCM were added. The layers were separated, and the organicphase was dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by reverse phase chromatography(water:CH₃CN 100:0 to 50:50) to afford 227 (10.5 mg, 19%). UPLC/MS(ES⁺):m/z 547.30 [M+H]⁺.

Example 94 Preparation of Compound 228

A mixture of 2-50 (50.0 mg, 0.110 mmol),7-fluoro-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole(108 mg, 0.270 mmol), Pd(dppf)Cl₂ (4.0 mg, 0.005 mmol) and aq. Na₂CO₃(2M solution, 135 uL, 0.270 mmol) in DCE (1 mL) was degassed and stirredwith heating to 85° C. for 5 h. Water and DCM were added, and the layerswere separated. The organic phase was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-51.

A solution of 2-51 in 10:1 DCM:TFA (1.1 mL) was stirred at r.t. for 3 h.A 1M aq. NaOH solution was added, and the mixture was stirred at r.t.for 18 h. The layers were separated, and the organic phase was driedwith Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography (water:CH₃CN 100:0to 50:50) to afford 228 (4.2 mg, 7% over 2 steps). UPLC/MS(ES⁺): m/z552.40 [M+H]⁺.

Example 95 Preparation of Compound 229

A mixture of 4-amino-3-hydroxybenzoic acid (2.01 g, 13.1 mmol), 12M aq.HCl solution (20 mL, 240 mmol) and 3-buten-2-one (1.59 mL, 19.6 mmol)was refluxed for 4 h. The volatiles were removed under reduced pressure,and the residue was purified by reverse phase chromatography(water:CH₃CN 100:0 to 0:100) to afford8-hydroxy-4-methylquinoline-6-carboxylic acid (830 mg, 31%). This wasdissolved in DMF (35 mL). Cesium carbonate (4.42 g, 13.6 mmol) andiodomethane (1.28 mL, 20.5 mmol) were sequentially added to thesolution. The mixture was stirred at r.t. for 4 h. The volatiles wereremoved under reduced pressure, and the residue was taken up with EtOAc.The organic portion was washed with water, dried with Na₂SO₄, filteredand concentrated under reduced pressure to afford crude 2-52 (860 mg),which was used in the next step without further purification.UPLC/MS(ES⁺): m/z 232.10 [M+H]⁺.

Lithium hydroxide monohydrate (280 mg, 6.73 mmol) was added to a stirredsuspension of 2-52 (220 mg) in a 2:1:1 THF:MeOH:H₂O mixture (4 mL). Themixture was stirred at r.t. for 1 h. The volatiles were removed underreduced pressure. The residue was dissolved in water, and the pH of theaqueous portion was adjusted to 6 with 1M aq. HCl solution. The mixturewas purified by reverse phase chromatography (water:CH₃CN 100:0 to0:100) to afford 2-53 (80 mg, 31%). UPLC/MS(ES⁺): m/z 218.10 [M+H]⁺.

Coupling of 2-53 with 2-30 according to Method A afforded 2-54, whichwas used in the next step without further purification.

Dess-Martin periodinane (127 mg, 0.299 mmol) was added to a stirredsolution of 2-54 (66 mg) in dry DCM (32 mL). The mixture was stirred atr.t. for 1 h. The reaction was quenched with a 1:1 1M aq. Na₂S₂O₃:sat.aq. NaHCO₃ solution, and the mixture was stirred vigorously for 30 mins.The layers were separated, and the organic portion was washed withbrine, dried with Na₂SO₄, filtered and concentrated under reducedpressure to afford crude 2-55, which was used in the next step withoutfurther purification.

A mixture of 2-55, (3-chloro-4-fluorophenyl)boronic acid (52.0 mg, 0.299mmol), Pd(dppf)Cl₂ (16.0 mg, 0.022 mmol) and aq. Na₂CO₃ (2M solution,222 uL, 0.447 mmol) in DCE (31 mL) was degassed and heated to 100° C.under microwave irradiation. After 2.5 h, the volatiles were removedunder reduced pressure. The residue was purified by reverse phasechromatography (water:CH₃CN 100:0 to 50:50) to afford 229 (10.0 mg).UPLC/MS(ES⁺): m/z 534.30 [M+H]⁺.

Example 96 Preparation of Compounds 230 and 231

Methyl magnesium bromide (3M solution in hexane, 300 uL, 0.892 mmol) wasadded to a solution of 3-1 (185 mg, 0.297 mmol) in dry THF (5 mL). Themixture was stirred at r.t. for 1 h. The reaction was quenched with 1Maq. HCl solution and EtOAc was added. The layers were separated, and theaqueous portion was extracted with EtOAc. The combined organic portionswere dried with Na₂SO₄, filtered and concentrated under reduced pressureto afford crude 3-2 (201 mg), which was used in the next step withoutfurther purification.

A solution of 3-2 (201 mg) in a 10:1 DCM:TFA (3 mL) was stirred at r.t.for 40 mins. The reaction was quenched with 1M aq. NaOH solution, andthe mixture was stirred at r.t. for 10 mins. The layers were separated,and the aqueous portion was extracted with DCM. The combined organicportions were dried with Na₂SO₄ and filtered. The volatiles were removedunder reduced pressure. Chromatography of the residue (EtOAc:MeOH 100:0to 80:20) afforded the two separated diastereomers (each as a racemicmixture, relative stereochemistry arbitrarily assigned). 230: whitesolid (10 mg, 7% overall) and UPLC/MS(ES⁺): m/z 519.30 [M+H]⁺. 231:white solid (37 mg, 24% overall) and UPLC/MS(ES⁺): m/z 519.30 [M+H]⁺.

Example 97 Preparation of Compound 232

To a solution of 232-1 (21.8 g, 69.9 mmol) and ethyl2,2,2-trifluoroacetate (12.9 g, 90.8 mmol) in THF (500 mL) was addedisopropyl-magnesium chloride (46.0 mL, 2.3 N in THF) at 0° C. Themixture was stirred at 0° C. for 30 mins. The reaction was quenched withsat. NH₄Cl solution and extracted with EA. The combined organic phaseswere dried over anhydride MgSO₄ and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel (PE:EA,5:1) to give 232-2 as an oil (16.5 g, 83.8%).

To a solution of 232-2 (16.5 g, 58.5 mmol),(3-chloro-4-fluorophenyl)boronic acid (10.51 g, 58.6 mmol), KF (7.1 g,117 mmol) in dioxane (300 mL) and H₂O (30 mL) was added Pd(dppf)Cl₂ (4.7g, 5.8 mmol). The mixture was degassed and then charged with nitrogen(3×). The mixture was stirred at 70° C. in an oil bath for 6 h under N₂.The mixture was cooled to r.t., diluted with EA and separated from thewater layer. The organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by column chromatography on silica gel (PE:EA, 10:1) to give232-3 as a white solid (17.0 g, 87.2%). ESI-MS: m/z 351.8 [M+H₂O]⁺.

A mixture of 232-3 (17.0 g, 51.1 mmol) and K₂CO₃ (13.8 g, 100 mmol) innitro-methane (100 mL) was stirred at r.t. for 10 h. The solution wasextracted with EA (3×200 mL). The combined organic phases were driedover anhydrous MgSO₄ and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using 15% EA in PEto give 232-4 as a white solid (16.0 g, 80.0%).

To a solution of 232-4 (16.0 g, 40.6 mmol) and NiCl₂.6H₂O (9.5 g, 40.4mmol) in anhydrous MeOH (150 mL) and anhydrous THF (150 mL) was addedNaBH₄ (15.2 g, 400.6 mmol) in portions at 0° C. After addition wascomplete, the solution was stirred at 0° C. for 1 h. The reaction wasquenched with H₂O and then extracted with EA (3×200 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography using EA to give 232-5 as an oil (11.0 g, 74.8%). ESI-MS:m/z 365 [M+H]⁺.

To a solution of (R)-3-chloro-4-(2-hydroxypropoxy)benzoic acid (115 mg,0.5 mmol), HATU (260 mg, 0.7 mmol) and DIPEA (320 mg, 2.5 mmol) inanhydrous DCM (5 mL) was added 232-5 (180 mg, 0.5 mmol) at 25° C. Thesolution was stirred for 1 h at 25° C. The mixture was diluted with 1.0N aqueous NaHCO₃ solution, and extracted with DCM (3×20 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by prep-HPLC to give 232 as a white solid (80 mg, 27.5%).ESI-MS: m/z 576.9 [M+H]⁺.

Example 98 Preparation of Compound 233

To a solution of 233-1 (1.8 g, 10.0 mmol) and F₃CCH₂I (2 g, 10.0 mmol)in DMF (100 mL) was added K₂CO₃ (2.6 g, 20.0 mmol). The mixture wasstirred at 80° C. for 3 h. The mixture was concentrated at low pressure,and the residue was dissolved in EA (50 mL). The mixture was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated to dryness. Thecrude product was purified by column chromatography using 10% EA in PEto give 233-2 (1.6 g, 60%).

To a solution of 233-2 (1.5 g, 5.7 mmol) in CH₃OH and water (120 mL and30 mL) was added LiOH (270 mg, 11.3 mmol). The mixture was stirred at70° C. for 2 h, and then cooled to r.t. The mixture was extracted withEA, and the residue was neutralized using 2.0 N HCl solution. Themixture was extracted with EA (3×30 mL). The organic layer was washedwith brine and dried over anhydrous Na₂SO₄. The solution wasconcentrated at low pressure to give 233-3 as a white solid (1.3 g,85%).

Compound 233 was prepared essentially as described in the preparation of232 by using 233-3 and 232-5. Compound 233 was obtained as a whitesolid. (100 mg, 67%) +ESI-MS: m/z 596.1 [M+H]⁺.

Example 99 Preparation of Compound 234

To a solution of 234-1 (1.0 g, 5.4 mmol) in MeCN (10 mL) were added1-chloro-2-propanone (1.0 g, 10.0 mmol) and K₂CO₃ (3.5 g, 20.0 mmol).The mixture was stirred at 80° C. for 1 h. After filtration, thefiltrate was concentrated at low pressure. The residue was purified bychromatography to give 234-2 (850 mg, 65.4%).

A mixture of 234-2 (500 mg, 2.1 mmol) and DAST (5 mL) was stirred at 50°C. for 12 h. The reaction was quenched with sat. NaHCO₃ solution, andextracted with EA (3×20 mL). The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated to dryness. The residuewas purified by column chromatography using 10% EA in PE to give 234-3(310 mg, 56.8%).

Compound 234-4 was prepared essentially as described in the preparationof 233-3. Compound 234 was prepared essentially as described in thepreparation of 232 by using 234-4 and 232-5. Compound 234 was obtainedas white solid (58 mg, 24.1%). +ESI-MS: m/z 593.1 [M+H]⁺.

Example 100 Preparation of Compound 235

To a solution of 235-1 (1.82 g, 10.0 mmol), tetrahydrofuran-3-ol (880mg, 10.0 mmol) and PPh₃ (2.62 g, 10.0 mmol) in THF (30 mL) at 0° C. wasadded DIAD (2.02 g, 10.0 mmol) dropwise. The mixture was stirred at 50°C. for 2 h, and the reaction was then quenched with sat. NaHCO₃solution. The aqueous layer was extracted by DCM (3×). The combinedorganic layers were dried over MgSO₄, filtered and concentrated at lowpressure. The residue was purified by flash column chromatography onsilica gel to give 235-2 (2.4 g, 89.6%).

Compound 235-3 was prepared essentially as described in the preparationof 233-3. Compound 235 was prepared essentially as described in thepreparation of compound 232 by using 235-3 and 232-5. Compound 235 wasobtained as white solid (75 mg, 62.3%). +ESI-MS: m/z 585.2 [M+H]⁺.

Example 101 Preparation of Compound 236

Compound 236 was prepared essentially as described in the preparation ofcompound 235 by using methyl 4-hydroxy-3-methoxybenzoate. Compound 236was obtained as white solid (56 mg, 22.7%). +ESI-MS: m/z 583.1 [M+H]⁺.

Example 102 Preparation of Compound 237

To a solution of 237-1 (0.93 g, 5 mmol) in acetone (30 mL) was addedK₂CO₃ (2.08 g, 15 mmol) and 2-iodoacetamide (1.39 g, 7.5 mmol). Themixture was stirred at r.t. overnight. The mixture was diluted withwater and extracted with EA (4×100 mL). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuum to give crude237-2, which was further purified by column chromatography on silica gel(PE:EA=2:1) to 237-2 (1.01 g, 83.1%) as a white solid.

Compound 237-3 was prepared essentially as described in the preparationof 233. Compound 237 was prepared essentially as described in thepreparation of 236 by using 237-3 and 232-5. Compound 237 was obtainedas white solid (32 mg, 22.2%). +ESI-MS: m/z 576.1 [M+H]⁺.

Example 103 Preparation of Compounds 238, 239 and 240

Compound 240 was prepared essentially as described in the preparation of232 by using 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid and 232-5.Compound 240 was obtained as a white solid (300 mg, 52.5%).

Compound 240 (300 mg, 0.53 mmol) was separated via SFC to give twoenantiomers: 238 (140 mg, 93.3%) and 239 (100 mg, 66.7%). Compound 238:+ESI-MS: m/z 572.1 [M+H]⁺. Compound 239: +ESI-MS: m/z 572.0 [M+H]⁺.

Example 104 Preparation of Compounds 241, 242 and 243

To a solution of 243-1 (714 mg, 2.0 mmol) in THF (4 mL) was addedcyclopropylmagnesium bromide (4 mL, 0.5 M in THF). The mixture wasstirred at 0° C. for 1 h. The reaction was quenched with water, andextracted with EA (3×20 mL). The combined organic layers was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated at low pressure.Crude 243-2 was directly used in the next step. +ESI-MS: m/z 399.0[M+H]⁺.

Compound 243-2 (600 mg), NH₃.H₂O (10 mL) and ethanol (10 mL) were put inan autoclave. After sealing, the reaction was stirred at r.t. for 10 h.The mixture was extracted by EA (3×10 mL), dried over anhydrous Na₂SO₄,and concentrated at low pressure to give 243-3, which was used withoutfurther purification. +ESI-MS: m/z 336.1 [M+H]⁺.

Compound 243 was prepared essentially as described in the preparation of232 by using 4-(2-hydroxyethoxy)-3-methoxybenzoic acid and 243-3.Compound 243 was obtained as a white solid (152 mg, 23%). +ESI-MS: m/z531.2 [M+H]⁺.

Compound 243 (152 mg, 0.28 mmol) was separated via SFC to give twoisomers: 242 (40.0 mg, 26%) and 241 (43.0 mg, 26%). 241: +ESI-MS: m/z531.1 [M+H]⁺. 242: +ESI-MS: m/z 531.1 [M+H]⁺.

Example 105 Preparation of Compound 244

Compound 244-2 was prepared as described in Franck et al., Bioorganic &Medicinal Chemistry, (2013) 21(3):643-652. Compound 244-3 was preparedessentially as described in the preparation of 235 by using 244-4 andmethyl 4-hydroxy-3-methoxybenzoate. Compound 244-3 was obtained as awhite solid (2.8 g, 73.7%).

To a solution of 244-3 (2.8 g, 8.2 mmol) in methanol (15 mL) was addedPd(OH)₂ on charcoal (10%, 500 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ (3×). The mixture was stirred under Fb(40 psi) at r.t. for 3 h. The suspension was filtered through a pad ofCelite, and the pad cake was washed with methanol. The combinedfiltrates were concentrated to give crude 244-4 (1.7 g, 84.5%), whichwas used in the next step without purification.

To a solution of 244-4 (1.3 g, 5.2 mmol) in DCM (10 mL) was added DMP(3.4 g, 8.0 mmol). The mixture was stirred at r.t. for 40 mins. Thereaction was quenched by sat. Na₂S₂O₃ solution and extracted with EA.The combined organic layers were washed with sat. NaHCO₃ solution, brineand dried over anhydrous Na₂SO₄. The solution was concentrated todryness, and the residue was purified by column chromatography on asilica gel column (PE:EA, 5:1) to give 244-5 as a white solid (0.8 g,61.6%).

Compound 244-5 (500 mg, 2.0 mmol) was treated with DAST (5 mL), andstirred at 0° C. for 30 mins. The reaction was quenched by a sat. NaHCO₃solution at 0° C., and then extracted with EA. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EA, 10:1) to give 244-6 as a whitesolid (605 mg, 81.2%). +ESI-MS: m/z 273.1 [M+H]⁺.

To a solution of 244-6 (300 mg, 1.1 mmol) in MeOH (35 mL) was added NaOHsolution (2 N, 35 mL). The reaction was stirred under reflux for 1 h.The mixture was neutralized with 2.0 N HCl solution, and extracted withEA (3×20 mL). The combined organic layers were dried over anhydrousMgSO₄ and evaporated under reduced pressure to give 244-7 as a whitesolid (250 mg, 88.1%). +ESI-MS: m/z 259 [M+H]⁺.

Compound 244 was prepared essentially as described in the preparation ofcompound 232 by using 244-7 and 232-5. Compound 244 was obtained as awhite solid (60 mg, 25.5%). +ESI-MS: m/z 606.1 [M+H]⁺.

Example 106 Preparation of Compound 245

Compound 245 was prepared essentially as described in the preparation of235. Compound 245 was obtained as a white solid (70 mg, 54.8%). +ESI-MS:m/z 569.1 [M+H]⁺.

Example 107 Preparation of Compound 248

Compound 248-2 was prepared as described in Rye et al., Eur. J. Med.Chem. (2013) 60:240-248. To a solution of 248-2 (6.0 g, 29.41 mmol) andK₂CO₃ (5.28 g, 38.23 mmol) in DMF (50 mL) was added methyl2,4-dibromobutanoate (9.86 g, 38.23 mmol). The mixture was stirred at80° C. for 12 h, and then diluted with water and extracted with EA (3×50mL). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel crude 248-3 (9.8 g).

To a solution of 248-3 (9.8 g, 25.8 mmol) in THF (100 mL) was addedt-BuOK (28.37 mL, 28.37 mmol, 1 N in THF) at 0° C. The mixture wasstirred at r.t. for 3 h. The mixture was diluted with water andextracted with EA (3×60 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by column chromatography to give 248-4 (6.0 g, 78.0%).

To a solution of 248-4 (6.0 g, 20.0 mmol) in EtOH (20 mL) was addedNaBH₄ (2.10 g, 30.0 mmol) at r.t. The mixture was stirred at r.t. for 10mins. The mixture was heated to reflux for 10 h and then cooled to r.t.The mixture was diluted with EA (60 mL) and washed with brine. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedat low pressure. The residue was purified by chromatography to give248-5 (4.5 g) as a white solid.

To a solution of 248-5 (500 mg, 1.84 mmol) in DCM (10 mL) was added Et₃N(370 mg, 3.68 mmol) and DMAP (10.0 mg, 0.082 mmol). TsCl (459 mg, 2.41mmol) was added portionwise. The mixture was stirred at r.t. overnight.The reaction was quenched with water, and extracted with EA (3×30 mL).The combined organic layer were dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by columnchromatography on silica gel to give 248-6 as a white solid (730 mg,93.1%).

To a solution of 248-6 (730 mg, 1.80 mmol) in anhydrous THF (10 mL) wasadded TBAF (1M in THF) (5.0 mL, 5.0 mmol). The mixture was stirred atr.t. overnight. The mixture was diluted with EA (20 mL) and washed withbrine. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by columnchromatography on silica gel to give 248-7 as a white solid (330 mg,67.0%).

To a solution of 248-7 (330 mg, 1.2 mmol) in anhydrous THF (10 mL) wasadded n-BuLi (0.63 mL, 1.6 mmol) at −78° C. dropwise. The mixture wasstirred at −78° C. for 0.5 h. CICOOCH₃ (0.69 g, 7.2 mmol) was added inone portion and stirred at −78° C. for 1 h. The mixture was diluted withEA (20 mL) and washed with brine. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by chromatography to give 248-8 as a white solid (203 mg,66.0%).

Compound 248-9 was prepared essentially as described in the preparationof 233. Compound 248 was prepared essentially as described in thepreparation of 232 by using 248-9 and 248-10. Compound 248 was obtainedas a white solid (12 mg, 3.7%). +ESI-MS: m/z 587.1 [M+H]⁺.

Example 108 Preparation of Compound 249

Compound 249-2 was prepared essentially as described in the preparationof 248. To a solution of 249-2 (1.02 mg, 2.5 mmol) in DMSO (10 mL) wasadded NaBH₄ (285 mg, 7.5 mmol) at r.t. under N₂ atmosphere. The solutionwas heated to 80° C. and stirred for 1 h. The solution was cooled tor.t. The reaction was quenched with water (20 mL) and extracted with EA(2×20 mL). The organic phase was concentrated at low pressure, and theresidue was purified by column chromatography on silica gel (PE:EA=20:1)to give 249-3 as a colorless oil (280 mg, 47.4%)

Compound 249-4 was prepared essentially as described in the preparationof 233. Compound 249 was prepared essentially as described in thepreparation of 232 by using 249-4 and 232-5. Compound 249 was obtainedas a white solid (7 mg, 13.7%). +ESI-MS: m/z 569.0[M+H]⁺.

Example 109 Preparation of Compound 250

Compound 250 was prepared essentially as described in the preparation of235 by using methyl 4-hydroxy-3-methoxybenzoate and 232-5. Compound 250was obtained as white solid (19.8 mg, 8.7%). +ESI-MS: m/z 571.0[M+H]⁺.

Example 110 Preparation of Compound 251

To a suspension of [IrCl(cod)]₂ (18 mg, 0.03 mmol) and sodium carbonate(171 mg, 1.6 mmol) in toluene (10 mL) was added 251-1 (500 mg, 2.68mmol) and vinyl acetate (457 mg, 5.38 mmol) under Ar. The mixture wasstirred at 100° C. for 2 h. The mixture was cooled to r.t., and treatedwith PE. The precipitate was removed by filtration, and the organicphase was concentrated at low pressure. The residue was purified bycolumn chromatography on silica gel (PE:EA=30:1) to give 251-2 (410 mg,72%).

TFA (468 mg, 4.1 mmol) was slowly added to anhydrous DCM (5 mL) andEt₂Zn (4.2 mL, 4.2 mmol) at 0° C. The mixture was stirred at 0° C. for10 mins, followed by the addition of CH₂I₂ (1.9 g, 7.1 mL). Theresulting solution was stirred at 0° C. for 10 mins, and then 251-2 (300mg, 1.42 mmol) was added. The mixture was allowed to warm to r.t., andstirred at r.t. overnight. The reaction was quenched with sat. NH₄Clsolution and extracted with EA (3×20 mL). The organic layer was driedover anhydrous MgSO₄ and concentrated at low pressure. The residue waspurified by column chromatography on silica gel (PE:EA=20:1) to give251-3 (210 mg, 65.8%).

Compound 251-4 was prepared essentially as described in the preparationof 233. Compound 251 was prepared essentially as described in thepreparation of 232 by using 251-4 and 232-5. Compound 251 was obtainedas white solid (23 mg, 10.1%). +ESI-MS: m/z 559.0[M+H]⁺.

Example 111 Preparation of Compound 252

Compound 252 was prepared essentially as described in the preparation of232 by using quinoline-6-carboxylic acid and 232-5. Compound 252 wasobtained as a white solid (70 mg, 33%). +ESI-MS: m/z 520.1 [M+H]⁺.

Example 112 Preparation of Compound 253

Compound 253 was prepared essentially as described in the preparation of232 by using 1H-benzo[d]imidazole-5-carboxylic acid and 232-5. Compound253 was obtained as a white solid (70 mg, 28%). +ESI-MS: m/z 509.1[M+H]⁺.

Example 113 Preparation of Compound 254

Compound 254 was prepared essentially as described in the preparation of232 by using benzo[d]thiazole-6-carboxylic acid and 232-5. Compound 254was obtained as a white solid (38 mg, 33%). +ESI-MS: m/z 525.9 [M+H]⁺.

Example 114 Preparation of Compounds 255, 256 and 398

To a solution of 255-1 (5 g, 27 mmol) and (R)-2-methyloxirane (4.7 g, 82mmol) in DMF (100 mL) was added K₂CO₃ (7.4 g, 54 mmol). The mixture wasstirred at 80° C. for 3 h. The reaction was quenched with water andextracted by EA (3×50 mL). The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by column chromatography on silica gel to give255-2 (6.5 g, 95%).

Compound 255-3 was prepared essentially as described in the preparationof 233. Compound 398 was prepared essentially as described in thepreparation of 232 by using 255-3 and 232-5. Compound 398 was obtainedas a white solid (687 mg, 68%).

Compound 398 (350 mg, 1.14 mmol) was separated via SFC to give twodiastereomers: 255 (113 mg) and 256 (107 mg). 255: +ESI-MS: m/z 573.1[M+H]⁺. 256: +ESI-MS: m/z 573.1 [M+H]⁺.

Example 115 Preparation of Compound 257

Compound 257-2 was prepared according to the procedure provided in Xu etal., Angew. Chem. Int. Ed (2011) 50(51): 12249-12252. Compound 257 wasprepared essentially as described in the preparation of 234 by using257-2 and 232-5. Compound 257 was obtained as a white solid (51 mg,23.8%). +ESI-MS: m/z 597.1 [M+H]⁺.

Example 116 Preparation of Compound 258

Compound 258 was prepared essentially as described in the preparation of232 by using 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acidand 232-5. Compound 258 was obtained as a white solid (80 mg, 41%).+ESI-MS: m/z 540.0 [M+H]⁺.

Example 117 Preparation of Compounds 259, 260 and 261

Compound 259-2 was prepared according to the procedure provided inChinese Patent No. CN 1869008, published Nov. 29, 2006, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 259-2. Compound 259-3 was prepared according to theprocedure provided in Barbayianni et al., J. Org. Chem. (2005)70(22):8730-8733, which is hereby incorporated by reference for thelimited purpose of its description of the preparation of 259-3. Compound259-4 was prepared essentially as described in the preparation of 235 byusing 259-3 and methyl 3-chloro-4-hydroxybenzoate. Compound 259-4 wasobtained as a white solid (4 g, 90%).

Under H₂ atmosphere, a mixture of 259-4 (4 g, 9 mmol) and Pd/C (200 mg)in MeOH (45 mL) was stirred at 30° C. for 10 h. Purification by columnchromatography on silica gel provided 259-4 (2 g, 80%). +ESI-MS: m/z269.8[M+H]⁺.

To a solution of 259-4 and 259-4A (2 g, 7.4 mmol) in THF/H₂O (10 mL/1mL) was added NaOH (400 mg, 10 mmol) in portions until the startingmaterial was consumed completely. The mixture was neutralized byaddition of 2 N HCl solution. The mixture was extracted with EA (3×40mL). The organic phase was washed with brine, dried over anhydrous MgSO₄and concentrated at low pressure to give 259-5 and 259-5A.

Compound 259-6 and 261 were prepared essentially as described in thepreparation of 232 by using 259-5 and 232-5. Compound 259-6 (100 mg) and261 (30 mg) were each obtained as a white solid. 261: +ESI-MS: m/z 568.1[M+H]⁺.

Compound 259-6 (100 mg, 0.16 mmol) was separated by SFC to give 259 (80mg, 80%) and 260 (20 mg, 20%). 259: +ESI-MS: m/z 602.1 [M+H]⁺. 260:+ESI-MS: m/z 602.1 [M+H]⁺.

Example 118 Preparation of Compound 262

Compound 262 was prepared essentially as described in the preparation of237 by using 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acidand 232-5. Compound 262 was obtained as a white solid (58 mg, 24.5%).+ESI-MS: m/z 563.0 [M+H]⁺.

Example 119 Preparation of Compounds 264 and 265

Compounds 264 and 265 were prepared essentially as described in thepreparation of 232 by using 1-methyl-1H-benzo[d]imidazole-6-carboxylicacid or 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid, and 232-5,respectively. Compounds 264 (47 mg, 26%) and 265 (51 mg, 28%) were eachobtained as a white solid. 264: +ESI-MS: m/z 522.9 [M+H]⁺. 265: +ESI-MS:m/z 523.0 [M+H]⁺.

Example 120 Preparation of Compound 266

Compound 266 was prepared essentially as described in the preparation of232 by using benzo[d]oxazole-6-carboxylic acid and 232-5. Compound 266was obtained as a white solid (60 mg, 23%). +ESI-MS: m/z 509.9 [M+H]⁺.

Example 121 Preparation of Compound 267

Compound 267 was prepared essentially as described in the preparation of232 by using3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid and232-5 as start material. Compound 267 was obtained as a white solid(10.7 mg, 7.6%). +ESI-MS: m/z 539.0 [M+H]⁺.

Example 122 Preparation of Compound 268

Compound 268 was prepared essentially as described in the preparation of232 by using1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid and232-5. Compound 268 was obtained as a white solid (14 mg, 8.4%).+ESI-MS: m/z 539.0 [M+H]⁺.

Example 123 Preparation of Compound 269

To a stirred solution of 269-1 (20.0 g, 130.68 mmol) in acetone (400 mL)was added KOH (18.4 g, 15 mmol) and (CH₃)₂SO₄ (29.4 mL, 318.9 mmol). Themixture was stirred at r.t. overnight. The solvent was evaporated at lowpressure, and the residue was dissolved in hot water. The pH wasadjusted to 9 with 1 N NaOH solution. After cooling to r.t., theprecipitate was filtered off and thoroughly washed with cold EtOAc togive 269-2 as a light yellow powder (23.66 g, 63.4%). +ESI-MS: m/z 181.8[M+H]⁺.

To a solution of 269-2 (14.4 g, 8 mmol) in EtOH (120 mL) was addedacetic anhydride (9.0 g, 88 mmol). The mixture was allowed to stir at50° C. for 2 h. The mixture was cooled to r.t., and neutralized withaqueous NaHCO₃ solution. The mixture was extracted with EA (3×60 mL).The organic phase was dried over anhydrous sodium sulfate, andconcentrated at low pressure. The residue was purified by flash columnchromatography on silica gel (PE:EA 1:1) to give 269-3 (15.0 g, 84.1%).+ESI-MS: m/z 223.9 [M+H]⁺.

To a solution of 269-3 (4.46 g, 20 mmol), PdOAc (0.45 g, 2 mmol) andCU(OAC)₂ (7.26 g, 40 mmol) in 1,2-dichloroethane (150 mL) was addedanhydrous CuBr₂ (8.93 g, 40 mmol) under N₂ atmosphere. The mixture wasstirred at 90° C. for 72 h. After cooling to r.t., the reaction wasquenched by water, and filtered through a celite pad. The solution waswashed with brine, dried by anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified by flash column chromatography onsilica gel (PE:EA 1:1) to give 269-4 (6.04 g, 51.3%). +ESI-MS: m/z 303.7[M+H]⁺.

To a solution of 269-4 (4.53 g, 15 mmol) in ethanol (60 mL) and water(60 mL) was added NaOH (6.0 g, 150 mmol), and the mixture was stirred at70° C. overnight. After cooling to 0° C., the mixture was neutralizedwith 5% aqueous HCl. The precipitate was filtered and concentrated togive 269-5 as a light yellow powder (3.1 g, 82.0%), which was usedwithout further purification. +ESI-MS: m/z 247.6[M+H]⁺.

A mixture of 269-5 (2.44 g, 10 mmol), glycerol (1.5 mL, 20 mmol), and3-nitrobenzenesulfonate (10 g, 45 mmol) were treated with cone. H₂SO₄(25 mL) and H₂O (8.3 mL). The mixture was heated at 100° C. for 3 h.,and then stirred at 140° C. for 1 h. The mixture was slowly cooled to60° C. Ethanol (15 mL) was added, and the mixture was stirred overnight.The mixture was neutralized with ammonia water, and extracted with EA(3×50 mL). The solution was dried over anhydrous Na₂SO₄ and concentratedat low pressure. The residue was purified by flash column chromatographyon silica gel (PE:EA 10:1) to give 269-6 (0.50 g, 16.9%). +ESI-MS: m/z295.9 [M+H]⁺.

To a stirred solution of 269-6 (0.295 g, 1 mmol) in DMF (3 mL) was addedK₂CO₃ (145 mg, 1.05 mmol) and CH₃I (149 mg, 1.05 mmol). The mixture wasstirred at r.t. overnight, and then concentrated at low pressure. Theresidue was dissolved in EA (20 mL). The solution was washed with brine,dried over Na₂SO₄ and concentrated in vacuum. The residue was purifiedby column chromatography on silica gel (PE:EA=5:1) to give 269-7 (216mg, 70.0%) as a white solid. +ESI-MS: m/z 311.9 [M+H]⁺.

To a stirred solution of 269-7 (240 g, 0.77 mmol) in methanol (30 mL)was added Pd/C (15 mg). The mixture was stirred at r.t. under H₂(balloon) for 1 h. The mixture was filtered, and the filtrate wasconcentrated at low pressure. The residue was purified by columnchromatography on silica gel (PE:EA=5:1) to give 269-8 (101 mg, 56.0%)as a white solid. +ESI-MS: m/z 231.9 [M+H]⁺.

To a solution of 269-8 (0.1 g, 0.44 mmol) in CH₃OH (2 mL) and water (2mL) was added NaOH (80 mg, 2 mmol), and the mixture was stirred at 50°C. for 0.5 h. The mixture was cooled to 0° C., and the pH was adjustedto 5 using 5% HCl solution. The mixture was extracted with EA (3×20 mL).The organic layer was dried over anhydrous sodium sulfate, andconcentrated at low pressure to give crude 269-9 (66 mg, 75.8%) as awhite solid, which was used without further purification.

To a solution of 269-9 (66 mg, 0.325 mmol) in DCM (5 mL) were added DMF(1 drop) and (COCl)₂ (0.23 mL, 1.3 mmol). The mixture was stirred atr.t. for 2 h, and then concentrated at low pressure. The residue wastreated with a solution of 232-5 (117 mg, 0.325 mmol) and TEA (0.28 mL)in DCM (5 mL) at 50° C. The mixture was allowed to stir at r.t.overnight. The mixture was diluted with water, and extracted with EA(3×20 mL). The organic layer was dried over anhydrous sodium sulfate,and concentrated in vacuum. The residue was purified by HPLC to give 269as a white solid (25 mg, 14.0%). +ESI-MS: m/z 550.0 [M+H]⁺.

Example 124 Preparation of Compound 270

Compound 270-2 was prepared according to the procedure provided in Ryeet al., Eur. J. Med Chem. (2013) 60:240-248, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 270-2. To a stirred solution of 270-2 (18.0 g, 89.1mmol) in acetone (200 mL) were added ethyl 2-bromoacetate (29.6 g, 178.2mmol) and K₂CO₃ (36.9 g, 270 mmol). The mixture was stirred at 80° C.for 12 h. The mixture was diluted with water and extracted with EA. Theorganic layers were dried over anhydrous sodium sulfate, andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel to give crude 270-3 (25 g yield: 98%).

To a solution of 270-3 (11 g, 38.2 mmol) in anhydrous THF (100 mL) wasadded Ti(i-PrO)₄ (10.85 g, 38.2 mmol) under N2 at 0° C., and then EtMgBr(34.4 mL, 103.14 mmol) was added dropwise. The mixture was stirred atr.t. overnight. The reaction was quenched with water, and extracted withEA (3×60 mL). The organic layer was dried over anhydrous sodium sulfate,and concentrated at low pressure. The residue was purified by columnchromatography on silica gel to give 270-4 (4.2 g, 40.4%).

To a solution of 270-4 (2.5 g, 9.19 mmol) in DCM (20 mL) were added DHP(1.54 g, 18.38 mmol) and TsOH (158.2 mg, 0.92 mmol). The mixture wasstirred at r.t. overnight. The reaction was quenched with water, andextracted with DCM. The organic layer was dried over anhydrous sodiumsulfate and concentrated at low pressure. The residue was purified bycolumn chromatography on silica gel to give 270-5 as a white solid (2.6g, yield: 74.0%).

To a solution of 270-5 (1.5 g, 4.21 mmol) in anhydrous THF (15 mL) wasadded n-BuLi (2.0 mL, 5.0 mmol) at −78° C. dropwise. After the mixturewas stirred at −78° C. for 0.5 h, CICOOCH₃ (2.39 g, 25.28 mmol) wasadded in one portion. The mixture was stirred at −78° C. for 1 h, andthen diluted with EA (50 mL) and washed with brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated at lowpressure. The residue was purified by chromatography to generate 270-6as a white solid (820 mg, yield: 58%).

To a stirred solution of 270-6 (410 mg, 1.22 mmol) in EtOH/H₂O (3:1, 10mL) was added NaOH (195 mg, 4.88 mmol), and the mixture was stirred at50° C. for 1 h. The mixture was diluted with water and extracted withEA. The pH of aqueous layers was adjusted to 4.0 by adding 5% HClsolution. The aqueous phase was extracted with EA. The organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuum togive crude 270-7 (198 mg).

To a solution of 270-7 (200 mg, 0.62 mmol) in DMF (15 mL) were addedDIPEA (240 mg, 1.86 mmol) and HATU (236 mg, 0.62 mmol). The mixture wasstirred at r.t. for 30 mins, and then 232-5 (226 mg, 0.62 mmol) wasadded. The mixture was stirred at r.t. for 2 h, and then diluted withwater and extracted with EA (3×20 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated at low pressure. The residuewas purified by column chromatography on silica gel to give 270-8 (250mg, 60.4%).

To a solution of 270-8 (250 mg, 0.37 mmol) in EtOH (10 mL) was addedPPTS (19.4 mg, 0.075 mmol). The mixture was stirred at 70° C. for 2 h,and then diluted with EA (50 mL) and washed with brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated at lowpressure. The residue was purified by prep-HPLC to give 270 as a whitesolid (80 mg, 37.0%). +ESI-MS: m/z 585.1 [M+H]⁺.

Example 125 Preparation of Compounds 271, 272 and 314

A 1 L round bottom flask was charged with a mixture of 271-1 (15 g,86.71 mmol), (3-chloro-4-fluorophenyl) boronic acid (15 g, 86.03 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.0 g, 1.37mmol) and K₂CO₃ (23.7 g, 172 mmol) in dioxane/H₂O (450 mL/50 mL) underN₂ atmosphere. The mixture was heated to 100° C. for 2 h. The mixturewas cooled to r.t. and dioxane was evaporated under reduced pressure.The residue was diluted with EA and water. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure.Chromatography of the residue (PE:EtOAc 100:1 to 40:1) afforded 271-2 asa white solid (11 g, 47.8%).

To a solution of 271-2 (7.2 g, 26.9 mmol) in toluene (200 mL) was addedMeMgBr (27 mL, 81 mmol) in 5 mins. The solution was stirred for 30 minsat r.t. Ti(OiPr)₄ (8 mL, 27.3 mmol) was added slowly at r.t. Thesolution was bathed in 100° C. oil and stirred for 20 mins. The mixturewas cooled to r.t., and the reaction was quenched with a sat. aq. Na₂CO₃solution. The mixture was separated by filtration, and the cake waswashed with EA. The organic phase was concentrated to dryness, and crude271-3 (7.0 g, brown oil) was used directly in the next step.

To a solution of 271-3 (7.0 g, 23.4 mmol) in toluene (100 mL), Et₃N(7.09 g, 70.2 mmol) and Boc₂O (5.6 g, 25.7 mmol) were added at r.t. Thesolution was bathed in 100° C. oil and stirred for 3 h. The solution wascooled to r.t., and separated between EA (300 mL) and water (200 mL).The organic phase was washed with brine and dried over Na₂SO₄. Theorganic phase was concentrated, and the residue was purified bychromatography on silica gel (PE:EA 20:1-10:1) to give 271-4 as a yellowsolid (7.05 g, 75.5%). +ESI-MS: m/z 398.9 [M+H]⁺.

To a solution of 271-4 (7.0 g, 17.5 mmol) in EtOH (70 mL) were addedK₂CO₃ (3.62 g, 26.2 mmol) and potassium trifluoro(vinyl)borate (2.8 g,21.0 mmol) at r.t. Pd(dppf)Cl₂ (256 g, 0.35 mmol) was added under N₂atmosphere. The mixture was bathed in 100° C. oil and stirred for 3 h.The solution was concentrated at low pressure, and the residue wasseparated between EA (100 mL) and water (50 mL). The organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified by chromatography on silica gel(PE:EA 20:1-10:1) to give 271-5 as a yellow oil (6.1 g, 89.3%). +ESI-MS:m/z 391.0 [M+H]⁺.

A solution of 271-5 (6.1 g, 15.6 mmol) in DCM (150 mL) was bubbled withO₃ at −78° C. until the solution turned blue. The solution was thenbubbled with N₂ until the blue colour disappeared. PPh₃ (4.9 g, 18.72mmol) was added at −78° C., and stirred for 2 h at −78° C. The mixturewas concentrated at low pressure, and the residue was purified bychromatography on silica gel (PE:EA 10:1-5:1) to give 271-6 as a whitesolid (4.8 g, 78.4%).

To a solution of 271-6 (4.86 g, 12.38 mmol) in dry DMF (25 mL) was addedTMSCF₃ (4.4 g, 31.0 mmol). The mixture was cooled down to −78° C., andTBAF (1M in THF, 7.3 mL, 7.3 mmol) was added dropwise. The mixture wasallowed to gradually warm to r.t., and stirred for 0.5 h. The mixturewas diluted with water and EtOAc. The organic layers was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Chromatographyof the residue (PE:EtOAc 100:0 to 80:20) afforded 271-7 (4.1 g, 72%).

To a stirred solution of 271-7 (4.1 g, 8.86 mmol) in dry DCM (45 mL) wasadded Dess-Martin periodinane (4.96 g, 17.7 mmol). The mixture wasstirred at r.t. for 10 h. The mixture was concentrated under reducedpressure and chromatography of the residue (PE:EtOAc 100:0 to 70:30)afforded 271-8 (3.8 g, 93%).

To a solution of 271-8 (3.8 g, 8.25 mmol) in MeNO₃ (10 mL) was addedEt₃N (2 mL, 14 mmol), and the mixture was stirred at r.t. for 30 mins.The mixture was concentrated under reduced pressure, and the residue wasdissolved in co-solvent of EtOH:H₂O (50 mL:5 mL). The mixture wastreated with iron powder (1.85 g, 33 mmol) and NH₄Cl (1.8 g, 33 mmol),and then heated to 80° C. for 2 h. After filtration, the solution wasconcentrated under reduced pressure. The residue was purified bychromatography to give 271-10 (2.5 g, 61.7%). +ESI-MS: m/z 491.9 [M+H]⁺.

A 100 mL round bottom flask was charged with a solution of4-cyclopropoxy-3-methoxybenzoic acid (208 mg, 1.0 mmol), DIPEA (193 mg,1.5 mmol) and HATU (380 mg, 1.0 mmol) in anhydrous DMF (10 mL). Themixture was stirred at r.t. for 30 mins. Compound 271-10 (490 mg, 1.0mmol) was added in one portion, and the mixture was stirred at r.t. for2˜3 h. The mixture was diluted with EA and water, and the organic phasewas washed with brine, dried over anhydrous sodium sulfate andconcentrated at low pressure. The residue was purified by columnchromatography on silica gel (PE:EA 1:1) to give 271-11 as a pale yellowoil (610 mg, 88%).

A 50 mL round bottom flask was charged with a solution of 271-11 (610mg, 0.88 mmol) in EA (10 mL). The solution was treated with HCl in EA(10 mL, 4.0 M). The mixture was stirred at r.t. for 1˜2 h. The mixturewas concentrated at low pressure to give crude 314 (550 mg).

Compound 314 (550 mg) was separated via SFC separation to give twoenantiomers. The two enantiomers were treated with 2 M HCl in EA andthen concentrated to give 271 (120 mg) and 272 (124 mg). 271: +ESI-MS:m/z 582.1 [M+H]⁺. 272: +ESI-MS: m/z 582.1 [M+H]⁺.

Example 126 Preparation of Compound 273

Compound 273 was prepared essentially as described in the preparation ofcompound 272 by 273-1 and 273-2. Compound 273 was obtained as a whitesolid (41 mg, 52.2%). +ESI-MS: m/z 554.0 [M+H]⁺.

Example 127 Preparation of Compounds 274-285

The following compounds in Table 1 were prepared essentially asdescribed in the preparation of 272 by using the listed acid and amine.

TABLE 1 Yield and Compound Acid Amine +ES-MS: m/z

benzo[d][1,3]dioxole-5- carboxylic acid 273-2 32 mg, 58.8% 539.9 [M +H]⁺

2,2- difluorobenzo[d][1,3]dioxole- 5-carboxylic acid 273-2 38 mg, 46.5%576.0 [M + H]⁺

2-chlorothiazole-5- carboxylic acid 273-2 30 mg, 54.5% 536.9 [M + H]⁺

thiazole-4-carboxylic acid 273-2 32 mg, 64.0% 502.9 [M + H]⁺

thiazole-5-carboxylic acid 273-2 18 mg, 36.0% 502.9 [M + H]⁺

2-methylthiazole-4- carboxylic acid 273-2 23 mg, 45% 517.0 [M + H]⁺

2-chlorothiazole-4- carboxylic acid 273-2 24 mg, 45% 537.0 [M + H]⁺

3-chloro-4-((2- oxopyrrolidin-3- yl)oxy)benzoic acid 273-2 28 mg, 45%629.0 [M + H]⁺

3-chloro-4- cyclopropoxybenzoic acid 273-2 20 mg, 34% 585.9 [M + H]⁺

(S)-3-methoxy-4-((2- oxopyrrolidin-3- yl)oxy)benzoic acid 273-2 28 mg,45% 625.1 [M + H]⁺

4-(cyclopropylmethoxy)-3- methoxybenzoic acid 273-2 30 mg, 68.2% 596.1[M + H]⁺

(R)-3-methoxy-4-((2- oxopyrrolidin-3- yl)oxy)benzoic acid 273-2 28 mg,45% 625.0 [M + H]⁺

Example 128 Preparation of Compound 286

Compound 286-2 was prepared according to the procedure provided in PCTPublication No. WO 2009/005638, published Jan. 8, 2009, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 286-2.

To a solution of 286-2 (1.83 g, 7 mmol) in THF (15 mL) was added n-BuLi(7 mL, 2.5 M in THF) at −78° C. After 5 mins, TMEDA (1.624 g, 14 mmol)was added at −78° C. The solution was warmed slowly to −30° C., andstirred for 30 mins at −30° C. The solution was cooled to −78° C. andoxirane (0.7 mL, 14 mmol) was added. The solution was stirred at −78° C.for 2 h., and stirred overnight at r.t. The reaction was quenched withH₂O and extracted with EA (2×30 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified by column chromatography (PE:EA 10:1)to give 286-3 (0.7 g, 32.7%).

To a solution of 286-3 (4.5 g, 14.7 mmol) in DCM (100 mL) was added TEA(4.45 g, 44.1 mmol). After cooled to 0° C., MsCl (3.36 g, 29.4 mmol) wasadded slowly. The solution was stirred for 30 mins. The reaction wasquenched with H₂O, and extracted with DCM (3×100 mL). The organic phasewas washed with brine, dried over anhydrate sodium sulfate andconcentrated at low pressure to give crude 286-4 (5.6 g, 99.2%).+ESI-MS: m/z 384.8 [M+H]⁺.

To a solution of 286-4 (5.6 g, 14.5 mmol) in DMF (50 mL) was added K₂CO₃(4.02 g, 29.2 mmol). The mixture was heated up to 50-60° C., and stirredfor 1 h. The solution was cooled to r.t., poured into cold water andextracted with EA (2×100 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by chromatography (PE:EA 10:1) to give 286-5 (3.1g, 74.3%).

To a solution of 286-5 (1.68 g, 5.83 mmol), 286-6 (860 mg, 5.83 mmol)and K₂CO₃ (1.61 g, 11.66 mmol) in MeOH (50 mL) was added Pd(dppf)Cl₂(426 mg, 0.583 mmol). The mixture was degassed and then refilled with N2(3 times). The mixture was stirred under nitrogen at 70° C. for 15 h,and then cooled to r.t., and extracted with EA (3×50 mL). The organicphase was washed by brine, dried over anhydrous Na₂SO₄ and concentratedat low pressure. The residue was purified by column chromatography(PE:EA 5:1) to give 286-7 as a white solid (1.2 g, 70%).

To a solution of 286-7 (2.94 g, 10 mmol) in DCM (50 mL) were added NMO(2.4 g, 20 mmol) and OsO₄ (500 mg, 0.2 mmol) at r.t. The mixture wasstirred at r.t. for 1 h. The reaction was quenched with sat. aq. Na₂S03,and stirred for 2 h. The mixture was extracted with DCM (2×100 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated at low pressure. The residue was purified bycolumn chromatography (PE:EA 3:1) to give 286-8 (2.94 g, 89.6%).+ESI-MS: m/z 328.9 [M+H]⁺.

To a solution of 286-8 (3.28 g, 10 mmol) and TEA (4.45 g, 44.1 mmol) inDCM (20 mL) was added MsCl (2.2 g, 20 mmol) slowly at 0° C. The solutionwas stirred for 30 mins, and then diluted with DCM (20 mL). The solutionwas washed with brine and dried over anhydrous sodium sulfate. Theorganic phase was concentrated at low pressure to give crude 286-9 (4.06g, 100.0%).

A solution of 286-9 (4.0 g, 10 mmol) in ammonia water and ethanol (10mL: 10 mL) in a seal tube was stirred for 1 h at r.t. The solution washeated to 40° C. for 15 h. The mixture was concentrated to dryness underreduced pressure to give crude 286-10 (1.6 g, 50%), which was usedwithout purification. +ESI-MS: m/z 327.9 [M+H]⁺.

To a solution of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (214 mg, 1mmol), HATU (456 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) in anhydrousDMF (5 mL) was added 286-10 (327 mg, 1 mmol) at 25° C. The solution wasstirred for 2 h at 25° C. The reaction was quenched by a sat. aq. NaHCO₃solution (40 mL), and then extracted with EA (2×20 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE:EA 3:1) to give 286-11 (201 mg, 38.2%).+ESI-MS: m/z 524.0 [M+H]⁺.

To a solution of 286-11 (150 mg, 0.3 mmol),(3-chloro-4-fluorophenyl)boronic acid (105 mg, 0.6 mmol) and K₂CO₃ (84mg, 0.6 mmol) in dioxane (6 mL) was added Pd(dppf)Cl₂ (22 mg, 0.03mmol). The mixture was degassed and then refilled with N2 (3 times). Themixture was heated to 120° C. by microwave under N2 for 2 h. Thesolution was cooled to r.t. and diluted with EA (20 mL). The solutionwas washed with brine, dried over anhydrous Na₂SO₄ and concentrated atlow pressure. The residue was purified by column chromatography (PE:EA1:1) to give 286-12 (123 mg, 65%).

To a solution of 286-12 (123 mg, 0.2 mmol) in DCM (2 mL) was added TFA(4 mL) at r.t. The mixture was stirred for 30 mins, concentrated todryness and dissolved in EA (20 mL). The solution was washed with a sat.NaHCO₃ solution. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by prep-HPLC to give 286 (80 mg, 77.6%) as a yellow solid.+ESI-MS: m/z 518.1 [M+H]⁺.

Example 129 Preparation of Compound 287

Compound 287 was prepared essentially as described in the preparation of286 by using7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indoleand 287-1. Compound 287 was obtained as white solid. +ESI-MS: m/z 507.9[M+H]⁺.

Example 130 Preparation of Compounds 288 and 289

To a solution of 135 (400 mg, 0.80 mmol) in THF (10 mL) was added MeMgBr(3 mL, 1.3 N in THF) under N₂. The mixture was stirred at r.t. for 1 hunder N₂. The reaction was quenched with sat. aq. NH₄Cl and extractedwith EA (3×20 mL). The combined organic layers were dried over anhydroussodium sulfate and evaporated under reduced pressure. The residue waspurified by prep-HPLC to give 288-1 (150 mg).

Compounds 288 (39 mg) and 289 (41 mg) were obtained by SFC separation of288-1. 288: +ESI-MS: m/z 519.3 [M+H]⁺. 289: +ESI-MS: m/z 519.3 [M+H]⁺.

Example 131 Preparation of Compound 290

To a solution of 286 (400 mg, 0.77 mmol) in DCM (20 mL) was added MnO₂(336 mg, 3.86 mmol) at r.t. The mixture was stirred for 2 h. Theprecipitate was removed by filtration, and the filtrate was concentratedat low pressure. The residue was purified by prep-HPLC to give 290 (150mg, 37.5%) as a yellow solid. +ESI-MS: m/z 515.9 [M+H]⁺.

Example 132 Preparation of Compounds 291 and 292

Compounds 291 and 292 were prepared essentially as described in thepreparation of 288 and 289 by using 291-1. Compound 291 (31 mg) and 292(30 mg) were obtained as white solids. 291: +ESI-MS: m/z 524.1 [M+H]⁺.292: +ESI-MS: m/z 524.1 [M+H]⁺.

Example 133 Preparation of Compounds 293 and 294

Compound 286 (60 mg) was separated via SFC separation to obtain twoenantiomers: 293 (24 mg) and 294 (22 mg). 293: +ESI-MS: m/z 517.9[M+H]⁺. 294: +ESI-MS: m/z 517.9 [M+H]⁺.

Example 134 Preparation of Compounds 295 and 296

Compound 290 (65 mg) was separated via SFC separation to obtain twoenantiomers: 295 (21 mg) and 296 (18 mg). 295: +ESI-MS: m/z 515.9[M+H]⁺. 296: +ESI-MS: m/z 515.9 [M+H]⁺.

Example 135 Preparation of Compound 297

To a solution of 297-1 (1.4 g, 5.0 mmol) and2-chloro-N-methoxy-N-methylacetamidein (700 mg, 5.0 mmol) in THF (20 mL)was added i-PrMgCl (3 mL, 2.0 M in THF) dropwise at 0° C. The mixturewas stirred at 0° C. for 1 h. The reaction was quenched with water, andextracted with EA (3×20 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuum. Theresidue was purified by column chromatography on silical gel to give297-2 (1.0 g, 87%). +ESI-MS: m/z 232.0 [M+H]⁺.

To a solution of 297-2 (460 mg, 2.0 mmol) in THF (4 mL) was addedcyclopropylmagnesium bromide (4 mL, 0.5 M in THF) dropwise at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction was quenched withwater, and extracted with EA (3×20 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuum. Compound 297-3 was used without further purification.

Compound 297 was prepared essentially as described in the preparation of286 by using 297-3. Compound 297 was obtained as white solid (98 mg).+ESI-MS: m/z 548.3 [M+H]⁺.

Example 136 Preparation of Compound 298

Compound 298-2 was prepared according to the procedure provided in PCTPublication No. WO 2009/016460, published Feb. 5, 2009, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 298-2. To a solution of 298-2 (1.8 g, 8.3 mmol) inDCM (10 mL) was added DAST (2 mL) dropwise at 0° C. The mixture wasstirred at r.t. for 30 mins. The reaction was quenched with sat. NaHCO₃solution at 0° C. and extracted with EA (3×30 mL). The combined organiclayers were washed by brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel column (PE:EA 30:1) to give 298-3 as awhite solid (1.4 g, 77.8%).

To a solution of 298-3 (1.4 g, 6.4 mmol) in THF (10 mL) was added n-BuLi(3.3 mL, 2.5 N in hexane) dropwise at −78° C. under N₂. The mixture wasstirred at −78° C. for 30 mins.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 9.4 mmol)was added at −78° C., and the mixture was allowed to warm to r.t., andstirred 10 mins. The reaction was quenched with sat. NH₄Cl solution andextracted with EA. The combined organic solutions were washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (PE:EA 50:1) to give 298-4 as an oil (1.0 g, 58.9%).

Compound 298 was prepared essentially as described in the preparation of286 by using 298-4. Compound 298 was obtained as a white solid (70 mg).+ESI-MS: m/z 555.1 [M+H]⁺.

Example 137 Preparation of Compound 299

Compound 299 was prepared essentially as described in the preparation of288 and 289 by using 298 and cyclopropylmagnesium bromide. Compound 299(30 mg) was obtained as a white solid. +ESI-MS: m/z 597.2 [M+H]⁺.

Example 138 Preparation of Compounds 300 and 301

Compound 229 (28 mg, 0.047 mmol) was separated via SFC separation togive two enantiomers: 300 (3.8 mg) and 301 (4.5 mg) as white solids.300: +ESI-MS: m/z 595.0 [M+H]⁺. 301: +ESI-MS: m/z 595.0 [M+H]⁺.

Example 139 Preparation of Compound 335

To a solution of 335-1 (5.2 g, 20 mmol) in THF (50 mL) was added n-BuLi(16 mL, 20 mmol, 2.5M) at −78° C. under N₂. After stirred at −78° C. for0.5 h, a solution of I₂ (5.1 g 20 mmol) in THF (25 mL) was added slowly.The mixture was stirred at −78° C. for 1 h. The reaction was quenchedwith water and extracted with EA (3×50 mL). The combined organic phasewas washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE:EA 10:1) to give 335-2 (7.5 g, 95%).+ESI-MS: m/z 388.9 [M+H]⁺.

To a solution of 335-2 (3.88 g, 10.0 mmol) in DMF (50 mL) was addedsodium hydride (480 mg, 10 mmol, 60% in the mineral oil) at r.t. Themixture was stirred for 0.5 h and 3-chloro-2-methylprop-1-ene (1.0 g, 11mmol) was added dropwise. The mixture was stirred for 2 h. The reactionwas quenched with water and extracted with EA (2×30 mL). The combinedorganic phase was washed with brine, dried over anhydrous sodium sulfateand concentrated at low pressure to give crude 335-3 (4.4 g, 99%), whichwas used without further purification.

Under N₂ atmosphere, a mixture of 335-3 (4.4 g, 10 mmol), LiCl (420 mg,10 mmol), sodium formate (1.36 g, 20 mmol) and Pd(OAc)₂ (111 mg, 0.1mmol) in DMF (95 mL) was stirred at 100° C. for 2 h. After cooling tor.t, the mixture was diluted with EA (50 mL). The solution was washedwith brine, dried over anhydrous sodium sulfate and concentrated at lowpressure. The residue was purified by column chromatography on silicagel (PE:EA 10:1) to give 335-4 (1.5 g, 50%). +ESI-MS: m/z 316.9 [M+H]⁺.

Under N₂ atmosphere, a mixture of 335-4 (1.5 g, 5 mmol),tributyl(1-ethoxyvinyl)stannane (3.6 g, 10 mmol) and Pd(dppf)Cl₂ (180mg, 0.25 mmol) in toluene (15 mL) was stirred at 140° C. for 0.5 h.After cooling to r.t., the mixture was concentrated at low pressure. Theresidue was purified by column chromatography on silica gel (PE:EA 10:1)to give 335-5 (1.5 g, 88%). +ESI-MS: m/z 352.9 [M+H]⁺.

To a solution of 335-5 (1.5 g, 1.35 mmol) in THF/H₂O (30 mL/1 mL) wasadded NBS (2.70 g, 15 mmol) in portions. The mixture was diluted withwater and extracted with EA (3×30 mL). The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate and concentratedat low pressure. The residue was purified by column chromatography onsilica gel (PE:EA 10:1) to give 335-6 (1.5 g, 75%).

To a solution of 335-6 (400 mg, 1.0 mmol) in DMF (5 mL) was added CF₃TMS(1 mL) and LiOAc (10 mg 0.02 eq.). After addition, the mixture wasstirred at r.t. until 335-6 was consumed. The mixture was treated withammonia water (5 mL), and then stirred at r.t. for 0.5 h. The mixturewas diluted with EA (50 mL). The solution was washed with brine, driedover anhydrous sodium sulfate and concentrated at low pressure. Theresidue was purified by column chromatography on silica gel (PE:EA 1:1)to give 335-7 (205 mg, 50%). +ESI-MS: m/z 410.0 [M+H]⁺.

Compound 335 was prepared essentially as described in the preparation of286 by using 4-cyclopropoxy-3-methoxybenzoic acid and 335-7. Compound335 was obtained as a white solid (25 mg). +ESI-MS: m/z 594.1 [M+H]⁺.

Example 140 Preparation of Compound 302

To a stirring mixture of 302-1 (460 mg, 1.6 mmol) in DMF (2 mL,deoxygenated prior to use) were added PdCl₂(PPh₃)₂ (114 mg, 0.16 mmol)and tributyl(vinyl)stannane (500 mg, 1.6 mmol). The reaction was carriedout under microwave irradiation at 80° C. for 2 h. The mixture wascooled to r.t. and diluted with EtOAc. The mixture was washed withbrine:water:NaHCO₃. The mixture was dried over MgSO₄, filtered andconcentrated under reduced pressure. Crude 302-2 was purified via asilica gel column. LCMS: m/z 186.05 [M+H]⁺.

To a stirring mixture of 302-2 (170 mg, 0.915 mmol) in DMF (3 mL) wasadded NaH (37 mg, 0.915 mmol). The mixture was stirred for 10 minsbefore allyl bromide (96 μL, 1.09 mmol) was added. The mixture wasstirred for 1 h at r.t., and then diluted with EtOAc and a 10% NaHCO₃aq. solution. The mixture was worked-up with EtOAc. The crude waspurified via a silica gel column to afford 302-3 as a yellow oil. LCMS:m/z 226.05 [M+H]⁺.

To a stirring mixture of 302-3 (100 mg, 0.44 mmol) in CH₂Cl₂ at r.t.(3.5 mL) was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (12 mg, 0.014 mmol). The mixture was stirred for 3 hand then concentrated under reduced pressure. The crude was purified viaa silica gel column to afford 302-4 as a tan solid. LCMS: m/z 198.0[M+H]⁺.

To a stirring mixture of 302-4 (70 mg, 0.35 mmol) in DME (2 mL,deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronicacid (74 mg, 0.43 mmol), PdCl₂(PPh₃)₂, a solution of Cs₂CO₃ (0.4 mL,2.65 M). The mixture was carried out under microwave irradiation at 110°C. for 1 h and then diluted with EtOAc and water. A normal aqueousworkup was followed. The crude was purified via a silica gel column toafford 302-5 as a white solid. LCMS: m/z 292.0 [M+H]⁺.

To a stirring mixture of 302-5 (70 mg, 0.24 mmol) in CH₂Cl₂ (2 mL) atr.t. were added NaHCO₃ (114 mg, 1.7 mmol) and Dess-Martin periodinane(509 mg, 1.2 mmol). The mixture was stirred at r.t. until the alcoholwas consumed. The reaction was quenched with 5% NaHSO₃ and sat. NaHCO₃solution. The aqueous layer was extracted with EtOAc (2×25 mL). Theorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude was purified via a silica gel column toafford 302-6. LCMS: m/z 290.0 [M+H]⁺.

To a stirring mixture of 302-6 (40 mg, 0.138 mmol) in THF (2 mL) wereadded K₂CO₃ and nitromethane (25 mg, 0.42 mmol). The mixture was stirredovernight at r.t. The reaction was diluted with EtOAc and quenched withwater and brine. The aqueous layer was extracted with EtOAc (2×25 mL).The crude was purified via a silica gel chromatography to afford 302-7as a white solid; LCMS: m/z 351.0 [M+H]⁺.

To a stirring mixture of 302-7 (55 mg, 0.158 mmol) in EtOAc (0.5 mL) wasadded SnCl₂.2H₂O (106 mg, 0.47 mmol). The mixture was heated at refluxfor 1 h. The mixture was cooled and concentrated under reduced pressure.The crude was purified via a silica gel column to afford 302-8 as acolorless oil. LCMS: m/z 321.0 [M+H]⁺.

To a stirring mixture of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (33.8mg, 0.156 mmol) in DMF (0.5 mL) were added HATU (59.3 mg, 0.156 mmol)and DIPEA (40 mg, 0.26 mmol). The mixture was stirred at r.t. for 10mins. Compound 302-8 (50 mg, 0.156 mmol) in DMF (0.5 mL) was added, andthen the mixture was stirred for 10 mins. The reaction was quenched witha 10% aq. solution of NaHCO₃ (10 mL). The mixture was diluted with DCMand a normal aqueous work up with DCM was followed. The crude waspurified via prep-HPLC to afford 302-9 as a white solid. LCMS: m/z517.10 [M+H].

To a stirring mixture of 302-9 (30 mg, 0.058 mmol) in DCM (1 mL) at r.t.was added Dess-Martin periodinane (172 mg, 0.41 mmol). The mixture wasstirred at r.t. for 1 h and the reaction quenched with 5% NaHSO₃ and asat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2×25mL). The organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude product was purified via HPLC toafford 302 as a white solid. LCMS: m/z 515.05 [M+H].

Example 141 Preparation of Compound 303

Compound 303 was synthesized by reacting 302 under hydrogenationreaction conditions using Pd/C in EtOAc/EtOH. LCMS: m/z 517.1 [M+H].

Example 142 Preparation of Compound 304

To a stirring mixture of3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (40 mg, 0.12mmol) in DMF (0.5 mL) were added HATU (36 mg, 0.096 mmol) and DIPEA (25mg, 0.192 mmol). The mixture was stirred at r.t. for 10 mins. Compound304-1 (31 mg, 0.096 mmol) in DMF (0.5 mL) was added, the mixture wasstirred for 10 mins. The reaction was quenched with 10% NaHCO₃ (3 mL).The mixture was diluted with DCM and a normal aqueous workup with DCMwas followed. The crude was purified via prep-HPLC to afford 304-2 as awhite solid. LCMS: m/z 635.1 [M+H].

To a stirring mixture of 304-2 (30 mg, 0.047 mmol) in DCM (1 mL) at r.t.was added Dess-Martin periodinane (200 mg, 0.47 mmol). The mixture wasstirred at r.t. for 1 h, and the reaction was quenched with 5% NaHSO₃and a sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc(2×25 mL). The organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude was purified via HPLC toafford 304-3 as a white solid; LCMS: m/z 633.15 [M+H]⁺.

To a stirring mixture of 304-3 (20 mg, 0.031 mmol) in EtOH/EtOAc (1:1,10 mL) was added Pd/C (10 mg). The mixture was reacted under H₂ balloon.The mixture was filtered through a plug of celite, and the filtrate wasconcentrated under reduced pressure. Crude 304-4 was used withoutfurther purification; LCMS: m/z 635.15 [M+H]⁺.

To a stirring mixture of 304-4 in DCM (1 mL) at 0° C. was added TFA (0.3mL) dropwise. The mixture was stirred at r.t. for 10 mins and thendiluted with EtOAc. The reaction was quenched sat. NaHCO₃. The aqueouslayer was extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The product was purified viaprep-HPLC to afford 304 as a white solid. LCMS: m/z 515.10 [M+H]⁺.

Example 143 Preparation of Compound 305

To a stirring mixture of 305-1 (500 mg, 1.75 mmol) in DMF (8.8 mL) at 0°C. was added NaH (144 mg, 3.6 mmol). The mixture was stirred at 0° C.for 5 mins. Allyl bromide (222 mg, 1.75 mmol) was added, and the mixturewas stirred at 0° C. for 20 mins. The mixture was warmed to r.t. andstirred for 5 mins. The mixture was diluted with EtOAc and quenched withwater. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedvia a silica gel chromatography to afford 305-2. LCMS: m/z 325.9 [M+H]⁺.

To a stirring mixture of 305-2 (280 mg, 1.4 mmol) and AIBN (23 mg, 0.14mmol) in toluene (3.5 mL) under Ar at reflux was added a solution oftributyltin hydride (407 mg, 1.4 mmol) in toluene (1 mL) dropwise over 5mins. The mixture was stirred at reflux for 2 h. and then concentratedunder reduced pressure. The crude was purified via a silica gel columnto afford 305-3 as a colorless oil. LCMS: m/z 200.05 [M+H]⁺.

To a stirring mixture of 305-3 (170 mg, 0.85 mmol) in DME (2.4 mL,deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronicacid (163 mg, 0.94 mmol), PdCl₂(PPh₃)₂ (93 mg, 0.13 mmol) and a solutionof Cs₂C03 (0.6 mL, 4.25 M). The reaction was carried out under microwaveirradiation at 110° C. for 1 h. The mixture was diluted with EtOAc andwater. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedvia a silica gel column to afford 305-4 as a white solid. LCMS: m/z294.0 [M+H].

Compound 305-7 was prepared in three steps similarly to the methodsdescribed for the synthesis of 302. Coupling of 305-7 with3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid followed byalcohol oxidation and deprotection afforded 305. LCMS: m/z 515.10[M+H]⁺.

Example 144 Preparation of Compound 306

To a stirring mixture of 306-1 (30 mg, 0.047 mmol) in THF (0.45 mL) atr.t. under Ar was added cyclopropyl magnesium bromide (1.9 mL, 0.95mmol). The mixture was stirred for 30 mins and then diluted with EtOAc.The reaction was quenched with a sat. NH₄Cl solution. A normal aqueousworkup with EtOAc was followed. The crude was purified via a silica gelcolumn to afford 306-2. LCMS: m/z 675.20 [M+H]⁺.

To a stirring mixture of 306-2 (30 mg, 0.052 mmol) in DCM (1 mL) wasadded TFA (0.2 mL) at r.t. The mixture was stirred for 10 mins, and thenquenched with a cold sat. NaHCO₃ solution. The aqueous solution wasextracted with DCM. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude was purified via prep-HPLC to afford 306 as a white solid.LCMS: m/z 555.10 [M+H]⁺.

Example 145 Preparation of Compounds 307-312

TABLE 2 Example Method No. Structure LCMS: m/z Compound 306 307

529.10 [M + H]⁺ Compound 306 308

557.15 [M + H]⁺ Compound 306 309

557.15 [M + H]⁺ Compound 306 310

543.15 [M + H]⁺ Compound 298 311

543.15 [M + H]⁺ Compound 306 312

585.15 [M + H]⁺

Example 146 Preparation of Compound 313

To a stirring mixture of 313-1 (45 mg, 0.092 mmol) in THF (1 mL) at r.t.under Ar was added a solution of t-BuMgCl in THF (0.91 mL, 0.91 mmol).The mixture was cooled to r.t., diluted with EtOAc and quenched with asat. NH₄Cl solution. The mixture was stirred at r.t. for 20 mins and thelayers were separated. The aqueous layer was extracted with EtOAc. Theorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude was purified via silica gel column andfurther purified via prep-HPLC to afford 313 as a white solid. LCMS: m/z549.15 [M+H]⁺.

Example 147 Preparation of Compound 314

Methylmagnesium bromide (27 mL, 3.2 M in THF, 87 mmol) was added to asolution of 314-1 (5.0 g, 29 mmol) in Et₂O (80 mL) at 0° C. After 1 h ofstirring, titanium isopropoxide (8.2 mL, 29 mmol) was added, and thereaction was heated at 50° C. for 2 h. Copious quantities of celite wereadded to the mixture which was cooled to r.t. The mixture was basifiedwith 2N NaOH and filtered through celite and washing with CH₂Cl₂. Thelayers were separated, and the organic layer was concentrated. Themixture was re-dissolved in CH₂Cl₂ and extracted with 1N HCl (3×). Theaqueous extracts were basified with solid K₂CO₃ and back-extracted withEA. The combined organic layers were washed with brine, dried andconcentrated to provide crude 314-2 (3.25 g).

Crude 314-2 (3.28 g, 16 mmol) was dissolved in CH₂Cl₂. Benzylchloroformate (2.3 mL, 16 mmol) and DIPEA (3.0 mL, 18 mmol) were added,and the reaction was stirred at r.t. for 3 h. The mixture was washedwith 1N HCl, brine, dried (Na₂SO₄) and concentrated. The crude waspurified via a silica gel chromatography to afford 314-3 as a whitesolid.

To a stirring mixture of 314-3 (2 g, 5.9 mmol) in DME (10 mL,deoxygenated prior to using) were added4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(1.32 g, 5.9 mmol) and a solution of Cs₂CO₃ (6M, 3 mL), PdCl₂(dppf) (461mg, 0.59 mmol). The mixture was stirred at 110° C. under microwavereaction conditions for 1 h. The mixture was diluted with EtOAc andwater. A normal aqueous workup with EtOAc was followed. The crude waspurified via a silica gel chromatography (EtOAc:hex 0-20%) to afford314-4 (1.3 g), which was used without further purification.

To a stirring mixture of 314-4 (1.3 g, 3.2 mmol) in DME (5 mL,deoxygenated prior to using) were added 3-chloro-4-fluorophenylboronicacid (550 mg, 3.2 mmol), a solution of Cs₂CO₃ (6M, 1.5 mL), and PdCl₂(dppf) (230 mg, 0.32 mmol). The mixture was stirred at 110° C. undermicrowave reaction conditions for 1 h. The mixture was diluted withEtOAc and water. A normal aqueous workup with EtOAc was followed. Thecrude was purified via a silica gel chromatography (EtOAc:hex 0-20%) toafford 314-5. LCMS: m/z 493.05 [M+H]⁺.

To a stirring mixture of tert-butyl hydroxycarbamate (2 g, 15 mmol) inTHF (10 mL) at 0° C. was added TsCl (2.8 g, 15 mmol) and TEA (2.2 mL,15.8 mmol). The mixture was stirred at 0° C. for 20 mins, and thenwarmed to r.t. for 5 mins. The mixture was diluted with DCM and washedwith water. A normal aqueous workup with DCM was followed. The crude waspurified via a silica gel to afford tert-butyl tosyloxycarbamate as awhite solid.

To a stirring mixture of 314-5 (950 mg, 1.9 mmol) in t-BuOH:water (3:1,3 mL total volume) at r.t. were added potassium osmate dihydrate (105mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). Themixture was stirred at r.t. overnight, and then diluted with water andDCM. A normal aqueous work up with DCM was followed. The crude waspurified via a silica gel chromatography to afford 314-6 (1.3 g, 80%pure). LCMS: m/z 626.20 [M+H]⁺.

Compound 314-6 was dissolved in a solution of HCl (4N) in dioxane (10mL) at r.t. The mixture was stirred at r.t. The mixture was concentratedunder reduced pressure to afford crude 314-7, which was used withoutfurther purification. LCMS: m/z 526.05 [M+H]⁺.

To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid (350 mg,1.69 mmol) in DMF (1.5 mL) were added HATU (642 mg, 1.69 mmol) and DIPEA(735 mL, 4.2 mmol). The mixture was stirred at r.t. for 10 mins.Compound 314-7 in DMF (2 mL) was added, and then stirred for 10 mins.The reaction was quenched with a 10% aqueous solution of NaHCO₃ (10 mL),and then diluted with DCM. A normal aqueous work up with DCM wasfollowed. The crude was purified via prep-HPLC to afford 314-8 as awhite solid. LCMS: m/z 716.2 [M+H]⁺.

To a stirring mixture of 314-8 (602 mg, 0.84 mmol) in AcCN (3 mL) atr.t. were added NaI (630 mg, 4.2 mmol) and TMSCl (453 mg, 4.2 mmol). Themixture was warmed to 60° C. until the starting material disappeared.The mixture was cooled to r.t. and purified by silica gel chromatography(EtOAc:hex 0-50% and then MeOH:DCM 0-20%). The product was furtherpurified via prep-HPLC and then converted to the HCl salt to afford 314.LCMS: m/z 582.2 [M+H]⁺.

Example 148 Preparation of Compounds 315-317

TABLE 3 Example Method No. Structure LCMS: m/z Compound 314 315

570.10 [M + H]⁺ Compound 314 316

556.10 [M + H]⁺ Compound 314 317

600.15 [M + H]⁺

Example 149 Preparation of Compound 318

To a stirring solution of 318-1 (40 mg, 0.028 mmol) in EtOAc:EtOH:HOAc(5 mL:1.0 mL:0.1 mL) was added Pd/C (20 mg). The mixture was placedunder a H₂ balloon. The mixture was stirred for several hours until thestarting material was consumed. The mixture was filtered through a plugof celite, and the plug was washed with EtOAc (2×10 mL). The mixture wasconcentrated under reduced pressure and purified via prep-HPLC to afford318 as a white solid. LCMS: m/z 548.15 [M+H]⁺.

Example 150 Preparation of Compounds 319-322

TABLE 4 Example Method No. Structure LCMS: m/z Compound 318 319

591.15 [M + H]⁺ Compound 318 320

522.15 [M + H]⁺ Compound 318 321

577.15 [M + H]⁺ Compound 318 322

599.10 [M + H]⁺

Example 151 Preparation of Compound 323

To a solution of 323-1 (2.5 g, 14.2 mmol) in THF (10 mL) and MeOH (10mL) was added NaBH₄ (1.6 g, 42.1 mmol) at 0° C. The mixture was stirredat 0° C. for 30 mins. The reaction was quenched with 1.0 N HCl andextracted with EtOAc. The combined organic solutions were dried (MgSO₄)and evaporated under reduced pressure. The residue was purified on asilica gel column (PE:EA 5:1) to give 323-2 as a colorless oil (2.0 g,79.1%).

A solution of 323-2 (2.0 g, 11.2 mmol), methyl4-hydroxy-3-methoxybenzoate (2.1 g, 11.5 mmol) and PPh₃ (4.5 g, 17.3mmol) was stirred in dry THF (40 mL) at 0° C. under a N₂ atmosphere.DIAD (3.5 g, 17.5 mmol) added dropwise over a period of 5 mins, and thesolution was allowed to stir at 50° C. for 3 h. After disappearance ofthe starting material, the solvent was evaporated under reducedpressure. The residue was purified on by column chromatography on silicagel (PE:EA 10:1) to give 323-3 as a white solid (2.8 g, 73.7%); ¹H-NMR(CDCl₃, 400 MHz), δ=7.62-7.60 (dd, J=1.6 Hz, J=10.0 Hz, 1H), 7.53 (s,1H), 7.34-7.25 (m, 5H), 6.66 (d, J=8.4 Hz, 1H), 4.96-4.93 (m, 1H), 4.44(s, 2H), 4.36-4.32 (m, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.59-2.54 (m,4H).

To a mixture of 323-3 (2.8 g, 8.2 mmol) in MeOH (15 mL) was addedPd(OH)₂ on carbon (10%, 500 mg) under N2. The suspension was degassedunder vacuum and purged with H2 (3×). The mixture was stirred under H2(40 psi) at r.t. for 3 h. The suspension was filtered through a pad ofCelite, and the cake was washed with MeOH. The combined filtrates wereconcentrated to give crude 323-4 (1.7 g, 84.5%) which was used withoutpurification.

To a mixture of 323-4 (1.7 g, 6.7 mmol) in DCM (10 mL) was added DAST (3mL) at 0° C. The mixture was stirred at 0° C. for 30 mins. The reactionwas quenched by sat. aq. NaHCO₃ at 0° C. and then extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EA 15:1) to give 323-5 as a white solid(800 mg, 47.1%).

A solution of 323-5 (254 mg, 1.0 mmol) and aq. lithium hydroxide (2 N, 1mL) in THF (5 mL) was stirred at r.t. for 1 h. The mixture wasneutralized by using 2N HCl and extracted with EtOAc. The combinedorganic solutions were dried (MgSO₄), and evaporated under reducedpressure to give 323-6 as a white solid (100 mg, 41.6%).

Compound 323 was prepared similarly to the preparation of 314. LCMS: m/z614.15 [M+H]⁺.

Example 152 Preparation of Compound 324

To a stirring mixture of 324-1 (360 mg, 1.73 mmol) and NaF (7.3 mg,0.173 mmol) in toluene (2 mL) at reflux was addedtrimethylsilyl-2,2-difluoro-2-(fluorosulphonyl)acetate dropwise over 1h. The mixture was heated at reflux for 1 h and then cooled to r.t. Themixture was concentrated under reduced pressure and loaded into a silicagel column to afford 324-2. LCMS: m/z 259.05 [M+H]⁺.

To a stirring mixture of 324-2 (320 mg, 1.24 mmol) in THF:water (1.0mL:0.2 mL) at r.t. was added aq. LiOH (155 mg, 3.7 mmol). The mixturewas stirred for 2 d. The mixture was diluted with EtOAc and acidifiedwith 10% aqueous HCl solution. A normal aqueous work up with EtOAc wasfollowed. Crude 324-3 was used without further purification.

Compound 324 was prepared similarly to the preparation of 314. LCMS: m/z618.15 [M+H]⁺.

Example 153 Preparation of Compound 325

To a stirring mixture of 325-1 (0.5 g, 2.75 mmol) in DMF (7 mL) wereadded Cs₂CO₃ (1.35 g, 4.12 mmol), and 2,2,2-trifluoroethyl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (837 mg, 2.2 mmol). Themixture was heated at 55° C. overnight, and then diluted with EtOAc, andwashed with water. The aqueous layer was extracted with EtOAc, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudewas purified via a silica gel column to afford 325-2 as a white solid;LCMS: m/z 265.05 [M+H]⁺.

To a stirring mixture of 325-2 (300 mg, 1.13 mmol) in THF:water (1mL:0.1 mL) was added aq. LiOH. The mixture was stirred at r.t.overnight. The mixture was diluted with EtOAc and acidified with a 1NHCl aqueous solution. The aqueous layer was extracted with EtOAc, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Crude325-3 was used without further purification.

Compound 325 was prepared similarly to the preparation of 314. LCMS: m/z624.1 [M+H]⁺.

Example 154 Preparation of Compound 326

To a stirring mixture of acetic acid (5 mg, 0.083 mmol) in DMF (0.2 mL)were added HATU (3.1 mg, 0.083) and DIPEA (17 mg, 0.13 mmol). Themixture was stirred at r.t. for 5 mins. A solution of 326-1 in DMF (0.8mL) was added, and the mixture was stirred for 10 mins. The reaction wasquenched with a 10% aq. solution of NaHCO₃ (10 mL). The mixture wasdiluted with DCM, and a normal aqueous work up with DCM was followed.Crude product was purified via prep-HPLC to afford 326 as a white solid.LCMS: m/z 624.15 [M+H]⁺.

Example 155 Preparation of Compounds 327-329

TABLE 5 Example Method Structure LCMS: m/z Compound 314

554.10 [M + H]⁺ Compound 326

596.1 [M + H]⁺ Compound 326

562.15 [M + H]⁺ Compound 330

654.15 [M + H]⁺ Compound 306

501.10 [M + H]⁺ Compound 314

559.10 [M + H]⁺ Compound 334

573.15 [M + H]⁺ Compound 334

529.1 [M + H]⁺ Compound 334

586.05 [M + H]⁺ Compound 334

550.05 [M + H]⁺ Compound 334

612.1 [M + H]⁺ Compound 334

545.15 [M + H]⁺ Compound 334

609.10 [M + H]⁺ Compound 334

627.15 [M + H]⁺ Compound 334

626.15 [M + H]⁺ Compound 334

652.2 [M + H]⁺ Compound 334

598.1 [M + H]⁺

Example 156 Preparation of Compound 330

To a stirring mixture of 330-1 (20 mg, 0.034 mmol) in DCM (0.4 mL) wereadded TEA (7 mg, 0.069 mmol) and MsCl (1 drop). The mixture was stirredfor 20 mins and slowly warmed to r.t. The mixture was diluted with DCM,and the reaction was quenched with a sat. NaHCO₃ solution. The aqueouslayer was extracted with DCM. The organic layers were dried (Na₂SO₄),filtered and concentrated under reduced pressure. Crude product waspurified via prep-HPLC to afford 330 as a white solid. LCMS: m/z 660.10[M+H]⁺.

Example 157 Preparation of Compound 332

To a stirring mixture of 332-1 (8 mg, 0.014 mmol) in DMF (0.2 mL) wasadded DMF.DMA (0.2 mL). The mixture was stirred at 90° C. until thestarting material was consumed. The crude mixture was concentrated underreduced pressure and used without further purification.

To a stirring mixture of crude product from the previous step in DCM(0.5 mL) at 0° C. were added hydrazine monohydrate (0.1 mL) and HOAc(0.05 mL). The mixture was warmed to r.t. and then reflux for 30 mins.The mixture was cooled to r.t., and the reaction was quenched with asat. NaHCO₃ solution. The aqueous layer was extracted with DCM, driedover Na₂SO₄, filtered and concentrated under reduced product. Crudeproduct was purified via prep-HPLC to afford 332 as a white solid. LCMS:m/z 595.1 [M+H]⁺.

Example 158 Preparation of Compound 342

To a stirring mixture of 342-1 (50 mg, 0.15 mmol) in t-BuOH:water (3:1,1.3 mL) at 0° C. were added NMO (26 mg, 0.23 mmol) and potassium osmatedehydrate (5.5 mg, 0.016 mmol). The mixture was warmed to r.t.overnight, and then diluted with DCM and water. The aqueous layer wasextracted with DCM, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified on a silica gel column toafford 342-2 as a brownish oil (50 mg, 91% yield). LCMS: m/z 366.0[M+H]⁺.

To a stirring mixture of 342-2 (50 mg, 0.136 mmol) in DCM (1 mL) at 0°C. were added TsCl (52 mg, 0.273 mmol), TEA (60 μL, 0.41 mmol) and DMAP(2 crystals). The mixture was warmed to r.t. for 1 h and then dilutedwith DCM. The reaction was quenched with sat. NaHCO₃ solution. Theaqueous layer was extracted with DCM, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude was purified via a silicagel column to afford 342-3 (65 mg, 92% yield). LCMS: m/z 520.0 [M+H]⁺.

To a stirring mixture of 342-3 (128 mg, 0.246 mmol) in acetone (1 mL)was added LiBr (64 mg, 0.74 mmol). The mixture was stirred at reflux for2 h and loaded into a silica gel column to afford 342-4 as a colorlessoil (75 mg, 71% yield). LCMS: m/z 427.95 [M+H]⁺.

To a stirring mixture of 342-4 in DCM (1 mL) at 0° C. was added DAST (58mL, 0.44 mmol). The mixture was stirred at 0° C. for 30 mins and thenwarmed to r.t. for 5 mins. The reaction was quenched with a cold aq.NaHCO₃ solution. The aqueous layer was extracted with DCM, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crude waspurified via a silica gel column to afford 342-5 (56 mg, 74% yield).LCMS: m/z 429.95 [M+H]⁺.

To a stirring mixture of 342-5 (50 mg, 0.116 mmol) in DMF (2 mL) wereadded tetrabutylammonium azide (330 mg, 1.2 mmol) and tetrabutylammoniumiodide (5 mg). The mixture was stirred at 95° C. for 4 h. The mixturewas loaded onto a silica gel column, eluting with hexane:EtOAc to afford342-6 as a colorless oil. LCMS: m/z 393.0 [M+H]⁺.

To a stirring mixture of 342-6 (25 mg, 0.064 mmol) in THF:water (10:1,1.1 mL) was added triphenylphosphine (polymer-bound, 167 mg, 0.64 mmol).The mixture was stirred at 70° C. for 30 mins, cooled to r.t. andfiltered through a plug of celite. The plug was washed several timeswith EtOAc. The mixture was concentrated under reduced pressure and342-7 used without further purification. LCMS: m/z 367.0 [M+H]⁺.

To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid(18 mg, 0.079 mmol) in DMF (0.5 mL) were added HATU (36 mg, 0.095 mmol)and DIPEA (35 μL, 0.191 mmol). The mixture was stirred at r.t. for 10mins. A solution of 342-7 in DMF (0.5 mL) was added, and the mixture wasstirred at for 10 mins. The reaction was quenched with a 10% aq.solution of NaHCO₃ (10 mL). The mixture was diluted with DCM and anormal aqueous work up with DCM was followed. The crude was purified viaprep-HPLC to afford 342 as a white solid. LCMS: m/z 575.15 [M+H]⁺.

Example 159 Preparation of Compound 343

Compound 343 was prepared according to the method described for 342.LCMS: m/z 574.10 [M+H]⁺.

Example 160 Preparation of Compound 344

To a stirring mixture of 3-methoxy-4-((4-methoxybenzyl)oxy)benzoic acid(35 mg, 0.095 mmol) in DMF (0.5 mL) were added HATU (45 mg, 0.114 mmol)and DIPEA (35 μL, 0.19 mmol). The mixture was stirred at r.t. for 10mins. A solution of 344-1 in DMF (0.5 mL) was added, and the mixture wasstirred for 10 mins. The reaction was quenched with a 10% aq. solutionof NaHCO₃ (5 mL). The mixture was diluted with DCM and a normal aqueouswork up with DCM was followed. The crude was purified via a silica gelcolumn to afford 344-2 as a colorless oil. LCMS: m/z 637.15 [M+H]⁺.

To a stirring mixture of 344-2 in DCM (1 mL) was added TFA (0.4 mL). Themixture was stirred at r.t. until 344-2 was consumed. The reaction wasquenched with a cold sat. NaHCO₃ solution. The aqueous layer wasextracted with DCM, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified via a silica gel column to give344-3 as a colorless oil. LCMS: m/z 517.1 [M+H]⁺.

To a stirring mixture of 344-3 (30 mg, 0.058 mmol) in DCM was addedCs₂CO₃ (47 mg, 0.145 mmol) and 3-bromopyrrolidin-2-one (11.4 mg, 0.07mmol). The mixture was heated under microwave irradiation at 70° C. for1 h. The mixture was filtered through a plug of celite and washedseveral times with DCM. The mixture was concentrated under reducedpressure and further purified via HPLC to afford 344 as a white solid.LCMS: m/z 600.15 [M+H]⁺.

Example 161 Preparation of Compound 350

To a stirring mixture of 350-1 (57 mg, 0.21 mmol) in THF (1 mL) at 0° C.was added NaH (17 mg, 0.43 mmol). The mixture was stirred at 0° C. for 5mins, and then methyl iodide (61 mg, 0.43 mmol) was added. The mixturewas warmed to r.t. and then diluted with EtOAc. The reaction wasquenched with a sat. NH₄Cl solution. The aqueous layer was extractedwith EtOAc, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified via a silica gel column to give 350-2.LCMS: m/z 280.05 [M+H]⁺.

To a stirring mixture of 350-2 (50 mg, 0.17 mmol) in THF:MeOH:water(1:0.4:0.1) at r.t. was added aq. LiOH (36 mg, 0.86 mmol). The mixturewas stirred overnight at r.t. The mixture was diluted with EtOAc andacidified with a 1N HCl solution. The aqueous layer was extracted withEtOAc, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Crude 350-3 was used without further purification. LCMS: m/z266.05 [M+H]⁺.

Compound 350 was prepared similarly according to the methods for 349.LCMS: m/z 612.1 [M+H]⁺.

Example 162 Preparation of Compound 351

To a stirring mixture of 351-1 (15 mg, 0.0295 mmol) in DCM (1 mL) at 0°C. were added acetic anhydride (10 mg, 0.09 mmol), TEA (20 μl) and DMAP(1 crystal). The mixture was stirred at r.t. until the alcohol wasconsumed. The reaction was quenched with a sat. NaHCO₃ (5 mL). Theaqueous layer was extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude was purified via HPLC toafford 352 as a white solid. LCMS: m/z 549.10 [M+H]⁺.

Example 163 Preparation of Compound 352

To a stirring mixture of 352-1 (25 mg, 0.047 mmol) in DMF (0.1 mL) wasadded DMF. DMA (0.1 mL). The mixture was stirred at 60° C. until thestarting material was consumed. The mixture was cooled to r.t. andconcentrated under reduced pressure. The crude used was without furtherpurification. To the stirring crude in DCM at 0° C. were added HOAc (3drops) and methyl hydrazine (3 drops). The mixture was warmed to r.t.for 20 mins and heated to reflux. The mixture was cooled to r.t.,diluted with DCM and quenched with a cold sat. NaHCO₃ solution. Theaqueous layer was extracted with DCM (3×10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude was purifiedvia prep-HPLC to afford 352 as a white solid. LCMS: m/z 582.15 [M+H]⁺.

Example 164 Preparation of Compound 353

To a solution of 353-1 (53 mg, 0.11 mmol) in THF (4 mL) was added MeMgCl(1 mL). The mixture was stirred at 0° C. for 1 h. The reaction wasquenched with a sat. NH₄Cl solution. The organic layers was washed withbrine, dried over Na₂SO₄ and concentrated. The crude was purified byprep-HPLC to give 353 (20 mg, 40%) as a white solid. LCMS: m/z 469.3[M+H]⁺.

Example 165 Preparation of Compound 354

A solution of i-PrMgCl (2.75 mL, 3.84 mmol) in THF was added dropwise toa stirring mixture of 354-1 (1 g, 3.66 mmol) at −45° C. over 5 mins. Themixture was stirred for 1 h, and then cyclobutanone (256 mg, 3.66 mmol)in THF (1 mL) was added. The mixture was warmed to r.t. and stirredovernight. The mixture was diluted with EtOAc, and the reaction quenchedwith a sat. NH₄Cl solution. The aqueous layer was extracted with EtOAc,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude was purified via a silica gel column to afford 354-2 as acolorless oil. LCMS: m/z 218 [M+H]⁺.

To a stirring mixture of 354-2 (0.4 g, 1.83) in CH₃CN (4 mL) at 0° C.was added dropwise H₂SO₄ (conc.) (490 μL, 9.2 mmol) over 5 mins. Themixture was warmed to r.t. for 1 h and then warmed to 80° C. for 30mins. The mixture was cooled to r.t., and then diluted with EtOAc. Thereaction was quenched with a sat. NaHCO₃ solution. The aqueous layer wasextracted with EtOAc, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified via a silica gel column toafford 354-3 as a white solid. LCMS: m/z 258.95 [M+H]⁺.

Steps 3-6 were conducted in a similar manner as 314 to provide 354.LCMS: m/z 636.15 [M+H]⁺.

Example 166 Preparation of Compound 355

To a stirring mixture of 354 (16 mg, 0.025 mmol) in 4N HCl in dioxane (2mL) was added a 6N HCl aqueous solution. The mixture was heated undermicrowave irradiation at 120° C. for 1 h. The mixture was cooled tor.t., diluted with DCM and neutralized with a cold sat. NaHCO₃ solution.The aqueous layer was extracted with DCM, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified viaprep-HPLC to afford 355 as a white solid. LCMS: m/z 594.10 [M+H]⁺.

Example 167 Preparation of Compound 356

To a stirring mixture of 356-1 (0.3 g, 1 mmol) in DMF at r.t. were addedCs₂CO₃ (488 mg, 1.5 mmol), NaI (15 mg) and 1-bromo-2-fluoroethane (127mg, 1 mmol). The mixture was heated to 45° C. overnight. The mixture wasdiluted with EtOAc and quenched with water. The aqueous layer wasextracted with EtOAc, dried over Na₂SO₄ and concentrated under reducedpressure. The crude was purified via a silica gel column to afford356-2. LCMS: m/z 345.1 [M+H]⁺.

Compound 356 was prepared in 4 steps using the similar methods as 314.LCMS: m/z 628.15 [M+H]⁺.

Example 168 Preparation of Compounds 357-361 and 363

TABLE 6 Example Method Structure LCMS: m/z Compound 327

572.15 [M + H]⁺ Compound 334

591.10 [M + H]⁺ Compound 306

501.10 [M + H]⁺ Compound 352

568.15 [M + H]⁺ Compound 327

520.15 [M + H]⁺ Compound 383

553.10 [M + H]⁺

Example 169 Preparation of Compound 362

To a stirring mixture of 336 (20 mg, 0.035 mmol) in DCM (1 mL) at r.t.was added Dess-Martin periodinane (150 mg, 0.175 mmol). The mixture wasstirred at r.t. for 1 h and then quenched with 5% NaHSO₃ and a sat.NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2×25 mL).The organic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude was purified via HPLC to afford 362 as awhite solid. LCMS: m/z 571.1 [M+H]⁺.

Example 170 Preparation of Compound 364

Methylmagnesium bromide (1.4 M in THF, 0.50 mL, 0.68 mmol) was added toa solution of bromoketone (0.163 g, 0.45 mmol) in THF (2 mL) at 0° C.After 30 mins, the reaction was quenched with NH₄Cl and extracted withEA, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel (EA:hexane) to give 364-2(0.115 g, 68%). LCMS: m/z 375.95 [M+H]⁺.

To a solution of 364-2 (0.115 g, 0.31 mmol) in CH₂Cl₂ (3 mL) at 0° C.was added DAST (81 uL, 0.61 mmol). The solution was stirred for 1 h. Themixture was diluted with sat. NaHCO₃ and extracted with EA. The combinedorganic phase was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give364-3 (0.071 g, 61%). LCMS: m/z 377.95 [M+H]⁺.

To a solution of 364-3 (0.071 g, 0.19 mmol) in DMF (1 mL) was addedtetrabutylammonium azide (0.7 g, 0.94 mmol). The solution was stirredfor 3 h at 90° C. and then diluted with EA. The organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give364-4 (0.054 g, 84%). LCMS: m/z 339.05 [M+H]⁺.

To a solution of 364-4 (0.054 g, 0.16 mmol) in THF (1 mL) and water (1drop) was added polymer supported triphenylphosphine (0.5 g, 1.5 mmol).The solution was stirred for 2 h at 60° C. The mixture was diluted withEA and filtered to remove resin. The organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated to provide crude364-5 (0.032 g, 63%), which was used without further purification. LCMS:m/z 313.00 [M+H]⁺.

Diisopropylethylamine (52 uL, 0.31 mmol) was added to a solution of4-(2-fluoroethoxy)-3-methoxybenzoic acid (33 mg, 0.15 mmol), 364-5 (32mg, 0.10 mmol) HBTU (62 mg, 0.16 mmol) in DMF (1 mL). The solution wasstirred at r.t. for 3 h. The mixture was diluted with EtOAc, and washedwith 1N HCl, sat. Na₂CO₃ and brine, dried over MgSO₄ and concentratedunder reduced pressure. The crude was purified by reverse phase HPLC togive 364 (10.4 mg, 20%). LCMS: m/z 509.05 [M+H]⁺.

Example 171 Preparation of Compound 365

Diisopropylethylamine (0.13 mL, 0.75 mmol) was added to a solution of3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (33 mg, 0.15mmol), 365-1 (78 mg, 0.25 mmol) HATU (0.15 g, 0.40 mmol) in DMF (1 mL).The solution was stirred at r.t. for 3 h. The mixture was diluted withEtOAc, and washed with 1N HCl, sat. Na₂CO₃ and brine, dried over MgSO₄and concentrated under reduced pressure. The crude was purified bychromatography on silica gel (EA:hexane) to give 365-2. LCMS: m/z 627.20[M+H]⁺.

Compound 365-2 was deprotected using TFA (0.25 mL) in CH₂Cl₂ (1.0 mL) atr.t. for 8 mins. The reaction was quenched with cold NaHCO₃ andextracted with CH₂Cl₂. The crude was purified by reverse phase HPLC togive 365 (10.4 mg, 8%). LCMS: m/z 507.01 [M+H]⁺.

Example 172 Preparation of Compound 368

Compound 368-1 (5.0 g, 39 mmol) and solid NaHCO₃ (5.0 g, 60 mmol) weresuspended in water (40 mL) and heated to 90° C. Formaldehyde (10 mL) wasadded portionwise over 8 h and the reaction was heated at 90° C.overnight. The mixture was cooled to 0° C. and acidified to pH 1 with 6NHCl. The solution was stirred at 0° C. for 1 h. The reaction wasfiltered, and the filtrate extracted with EA to provide 368-2 (4.9 g,79%). ¹H NMR (400 MHz, CDCl₃): δ 7.21 (d, J=4.6, 1H), 7.20 (d, J=4.6,1H), 4.4 (s, 2H).

Iodomethane (4.5 mL, 72 mmol) was added to a solution of 368-2 (7.7 g,48 mmol) and potassium carbonate (13 g, 144 mmol) in DMF (60 mL). Themixture was stirred at 50° C. for 1 h. The mixture was diluted with EA,washed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give368-3 (2.57 g, 31%). ¹H NMR (400 MHz, CDCl₃): δ 7.20 (s, 2H), 4.6 (d,J=6.0, 2H).

Methanesulfonyl chloride (1.4 mL, 0.18 mmol) was added to a solution of368-3 (2.57 g, 15 mmol) and diisopropylethyl amine (3.9 mL, 22 mmol) inCH₂Cl₂ (30 mL) at 0° C. After 30 mins, the mixture was diluted withCH₂Cl₂, washed with 1N HCl and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was dissolved in DMF (10 mL) and treated withsodium cyanide (2.2 g, 44 mmol) at 80° C. for 3 h. The mixture wasdiluted with EA, and the organic phase was washed with water and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby chromatography on silica gel (EA:hexane) to give 368-4 (1.13 g, 41%).LCMS: m/z 183.03 [M+H]⁺.

Pd(dppf)Cl₂ (0.45 g, 0.61 mmol) was added to a solution of 368-4 (0.56g, 3.1 mmol), 3-chloro-4-fluorophenyl boronic acid (0.80 g, 4.6 mmol) inCH₃CN (10 mL) and 1M K₂CO₃ (5 mL). The reaction vessel was heated undermicrowave irradiation for 3 h at 120° C. The mixture was diluted withEA. The organic phase was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 368-5 (0.70 g, 81%).LCMS: m/z 277.05 [M+H]⁺.

Sodium hydride (76 mg, 1.9 mmol) was added to a solution of 368-5 (0.21g, 0.76 mmol) in DMF (1 mL). After 5 mins, iodomethane (0.14 mL, 2.3mmol) was added, and the mixture was stirred for 30 mins. The reactionwas quenched with NH₄Cl, diluted with EA. The organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give368-6 (0.19 g, 81%). LCMS: m/z 305.00 [M+H]⁺.

Lithium aluminum hydride (1.8 mL, 1M in THF, 1.8 mmol) was added to asolution of 368-6 (0.19 g, 0.61 mmol) in THF (5 mL), and the mixture wasstirred at r.t. for 2 h. The reaction was quenched by the addition ofsolid sodium sulfate decahydrate and stirred for 10 mins. The solidswere filtered, and the filtrate was concentrated to yield 368-7 (0.16 g,85%). LCMS: m/z 309.05 [M+H]⁺.

Compounds 368-8 and 368 were prepared in the same manner as 365.Compound 368-8: LCMS: m/z 624.3 [M+H]⁺. Compound 368: LCMS: m/z 503.15[M+H]⁺.

Example 173 Preparation of Compound 369

Methyl vanillate (0.25 g, 1.4 mmol) and vinyl acetate (0.25 mL, 2.7mmol) were added to [IrCl(cod)]₂ (9 mg, 0.014) and sodium carbonate (52mg, 0.49 mmol) in toluene (1 mL). The mixture was flushed with Ar andstirred at 110° C. for 1.5 h and then diluted with EA. The organic phasewas washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 369-1 (0.159 g, 55%). ¹H NMR (400 MHz, CDCl₃): δ7.61 (dd, J=1.6, 8.0, 1H), 7.0 (d, J=8.4, 1H), 6.63 (dd, J=6.0, 14, 1H),4.87 (dd, J=2.4, 14, 1H), 4.55 (dd, J=2.0, 6.0, 1H), 2.92 (s, 2H), 3.91(s, 3H).

Diethylzinc (9 mL, 9.0 mmol) was added dropwise to a solution of 369-1(0.234 g, 1.1 mmol) and diiodoethane (0.72 mL, 9.0 mmol) indichloroethane (3 mL) at 0° C. The mixture was stirred at r.t.overnight, and then diluted with EA. The organic phase was washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give369-2 (0.121 g, 55%). ¹H NMR (400 MHz, CDCl₃): δ 7.61 (dd, J=1.6, 8.0,1H), 7.0 (d, J=8.4, 1H), 6.63 (dd, J=6.0, 14, 1H), 4.87 (dd, J=2.4, 14,1H), 4.55 (dd, J=2.0, 6.0, 1H), 3.92 (s, 3H).

2N Sodium hydroxide (1 mL) was added to a solution of 369-2 (58 mg) inmethanol (3 mL), and the mixture was stirred at r.t. overnight. Themixture was acidified with 1N HCl and extracted with EA to give 369-3(50 mg, 86%). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=1.95, 1H), 7.58 (s,1H), 7.30 (d, J=1.95, 1H), 3.91 (s, 3H), 3.80-3.83 (m, 1H), 0.85-0.89(m, 4H).

Compound 369 was prepared in a similar manner as 364. LCMS: m/z 501.1[M+H]⁺.

Example 174 Preparation of Compound 371

Isobutylene (10 mL, 105 mmol) was added to a solution of methylvanillate (1 g, 5.5 mmol) and H₂SO₄ (3 drops) in CH₂Cl₂ (15 mL) in asealed vessel at −40° C. The mixture was warmed to r.t. and stirred over2-3 d. The mixture was diluted with EA. The organic phase was washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give371-2 (0.161 g, 12%). ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, J=6.26, 1H),7.63 (d, J=1.96, 1H), 7.09 (d, J=8.26, 1H), 3.88 (s, 3H), 3.87 (s, 3H),1.41 (s, 9H).

Compound 371 prepared in a similar manner as 364. LCMS: m/z 517.2[M+H]⁺.

Example 175 Preparation of Compound 372

Potassium fluoride (0.10 g, 1.7 mmol) and methyl vanillate (0.31 g, 1.7mmol) were mixed in methanol (5 mL) for 15 mins. The mixture wasconcentrated, co-evaporating with diethyl ether (2×). The residue wasdissolved in DMSO (2.0 mL) and added to difluoroiodoethane (0.36 g, 1.9mmol) in a vial. The vial was flushed with Ar, sealed, and heated at120° C. overnight. The mixture was diluted with EA. The organic phasewas washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 372-1 (0.060 g, 14%). ¹H NMR (400 MHz, CDCl₃): δ 766(dd, J=1.95, 8.41, 1H), 7.59 (d, J=1.95, 1H), 6.92 (d, J=8.41, 1H),6.00-6.30 (m, 1H), 4.24-4.31 (m, 2H), 3.91 (s, 3H), 3.91 (s, 3H).

Compound 372 was prepared in a similar manner as 364. LCMS: m/z 525.10[M+H]⁺.

Example 176 Preparation of Compound 374

Sodium iodide (1 mg) was added to a solution of methyl vanillate (0.26g, 1.4 mmol), bromocyclobutane (0.40 mL, 4.3 mmol), potassium carbonate(0.98 g, 4.3 mmol) in NMP (1.5 mL). The mixture was heated undermicrowave irradiation at 180° C. for 1.5 h and then diluted with EA. Theorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel (EA:hexane) to give 374-1 (0.18 g, 54%). ¹H NMR (400 MHz,CDCl₃): δ 7.3 (d, J=8.41, 1H), 7.53 (s, 1H), 6.74 (d, J=8.41, 1H),4.4-4.7 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H).

Compound 372-2 was hydrolyzed in a similar manner as 369, and 372 wasprepared in a similar manner as 364. LCMS: m/z 568.9 [M+H]⁺.

Example 177 Preparation of Compound 375

Tetrabutylammonium azide (0.33 g, 0.57 mmol) was added to 375-1 (60 mg,0.16 mmol) in DMF (1 mL), and the mixture was heated at 80° C. for 5 h.The mixture was diluted with EA. The organic phase was washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel (EA:hexane) to give 375-2(0.052 g, 96%). LCMS: m/z 337.05 [M+H]⁺.

NaH (12 mg, 0.31 mmol) was added to 375-2 (52 mg, 0.15 mmol) in DMF (1mL). The mixture was stirred at r.t. for 15 mins. Iodomethane (30 uL,0.46 mmol) was added, and the mixture reaction was stirred for 2 h. Themixture was diluted with EA, and the organic phase was washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel (EA:hexane) to give 375-3(0.052 g, 98%). LCMS: m/z 351.05 [M+H]⁺.

Compound 375 was prepared in a similar manner as 364. LCMS: m/z 539.15[M+H]⁺.

Example 178 Preparation of Compound 377

Pd(dppf)Cl₂ (20 mg, 0.02 mmol) was added to a solution of2,6-dichloro-3-fluoropyridine (0.20 g, 0.78 mmol) and1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (0.18 g, 0.86mmol) in CH₃CN (0.5 mL) and 1M K₂CO₃ (0.25 mL). The mixture was heatedunder microwave irradiation for 1 h at 110° C. The reaction was dilutedwith EA, and the organic phase was washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 377-1 (0.10 g, 47%).LCMS: m/z 271.90 [M+H]⁺.

Pd(dppf)Cl₂ (75 mg, 0.091 mmol) was added to 377-1 (0.493 g, 1.8 mmol)and 3-chloro-4-fluorophenyl boronic acid (0.38 g, 2.7 mmol) in CH₃CN (2mL) and 1M K₂CO₃ (0.5 mL). The mixture was heated under microwaveirradiation at 110° C. for 30 mins. The mixture was heated undermicrowave irradiation for 1 h at 110° C. The mixture was diluted withEA, and the organic phase was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 377-2 (0.286 g, 33%).LCMS: m/z 319.95 [M+H]⁺.

Potassium osmate (50 mg, 0.13 mmol) was added to a suspension of 377-2(0.286 g, 0.89 mmol) and tert-butyl (tosyloxy)carbamate (0.36 g, 1.3mmol) in t-butanol (2 mL) and water (0.6 mL), and the mixture wasstirred overnight at r.t. The crude was poured directly onto a silicagel column and chromatographed (EA:hexane) to give 377-3. (0.162 g,40%). LCMS: m/z 398.83 [M+H]⁺.

4N HCl in dioxane (2 mL) was added to 377-3 (0.16 g), and the mixturewas stirred at r.t. for 1 h. The mixture was concentrated to give 377-4,which was used without further purification. Compound 377 was preparedin a similar manner as 364. LCMS: m/z 506.20 [M+H]⁺.

Example 179 Preparation of Compound 378

NaH (0.13 g, 3.1 mmol) was added to a solution of methyl vanillate (0.44g, 2.4 mmol) and 2-iodopropane (1.2 mL, 12 mmol) in DMF (3.0 mL), andthe mixture was heated at 65° C. for 1 h. The mixture was diluted withEA, and the organic phase was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 378-1 (0.50 g, 93%). ¹HNMR (400 MHz, CDCl₃): δ 7.65 (dd, J=1.95, 8.6, 1H), 7.55 (d, J=1.96,1H), 6.90 (d, J=8.6, 1H), 4.61-4.66 (m, 1H), 3.91 (s, 3H), 3.58 (s, 3H),1.41 (s, 3H), 1.39 (s, 3H).

Compound 378-1 was hydrolyzed in a similar manner as 369 to give 378-2.¹H NMR (400 MHz, CDCl₃): δ 7.74 (dd, J=1.95, 8.6, 1H), 7.60 (d, J=1.96,1H), 6.92 (d, J=8.6, 1H), 4.65-4.68 (m, 1H), 3.92 (s, 3H), 1.41 (s, 3H),1.39 (s, 3H). Compound 378 was prepared in a similar manner as 364.LCMS: m/z 557.10 [M+H]⁺.

Example 180 Preparation of Compound 379

NaH (0.13 g, 3.1 mmol) was added to a solution of methyl vanillate (0.44g, 2.4 mmol) and chloromethylmethyl sulfide (0.24 mL, 2.8 mmol) in DMF(3.0 mL), and the mixture was stirred for 1 h. The mixture was dilutedwith EA, and the organic phase was washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 379-1 (0.57 g, 92%).

MCPBA (0.9 g, 5.2 mmol) was added to 379-1 (0.576 g, 2.4 mmol) in CH₂Cl₂(3 mL), and the mixture was stirred at r.t. for 1 h. The mixture waswashed with Na₂CO₃, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give379-2 (0.40 g, 70%).

Compound 379-2 was hydrolyzed in a similar manner as 369 to give 379-3.Compound 379 was prepared in a similar manner as 364. LCMS: m/z 553.10[M+H]⁺.

Example 181 Preparation of Compound 380

2-Bromoacetamide (0.46 g, 3.4 mmol) was added to methyl3-fluoro-4-hydroxybenzoate (0.29 g, 1.7 mmol) and potassium carbonate(0.70 g, 5.0 mmol) in DMF (1 mL), and the mixture was heated to 65° C.for 1 h. The mixture was diluted with EA, and the organic phase waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. Compound 380-1 was crystallized from EA and collected byfiltration (0.27 g, 71%). ¹H NMR (400 MHz, dmso-d₆): δ 7.67-7.42 (m,2H), 7.50 (br. s, 1H), 7.38 (br. s, 1H), 7.11 (t, J=8.62, 1H), 4.62 (s,2H), 3.79 (s, 3H).

Compound 380-1 was hydrolyzed in a similar manner as 369 to give 380-2.¹H NMR (400 MHz, dmso-d₆): δ 7.63-7.69 (m, 2H), 7.49 (br. s, 1H), 7.38(br. s, 1H), 7.08-7.11 (m, 1H), 4.61 (s, 2H). Compound 380 was preparedin a similar manner as 364. LCMS: m/z 560.05 [M+H]⁺.

Example 182 Preparation of Compound 381

2-Bromoacetamide (0.46 g, 3.4 mmol) was added to methyl3-bromo-4-hydroxybenzoate (0.46 g, 1.7 mmol) and potassium carbonate(0.70 g, 5.0 mmol) in DMF (1 mL), and the mixture was heated to 65° C.for 1 h. The mixture was diluted with EA, and the organic phase waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 381-1 (0.091 g, 24%). ¹H NMR (400 MHz, dmso-₆): δ7.95 (d, J=2.34, 1H), 7.90 (dd, J=2.34, 8.61, 1H), 7.45 (br. s, 1H),7.34 (br. s, 1H), 7.06 (d, J=8.61, 1H), 4.65 (s, 2H), 3.78 (s, 3H).

381-1 was hydrolyzed in a similar manner as 369-2 to give 381-2. ¹H NMR(400 MHz, dmso-d₆): δ 8.12 (d, J=2.34, 1H), 7.87 (dd, J=2.35, 6.0, 1H),7.15 (d, J=6.0, 1H), 4.87 (s, 2H).

Compound 381 was prepared in a similar manner as 364. LCMS: m/z 621.76[M+H]⁺.

Example 183 Preparation of Compound 382

Diisopropylethylamine (0.15 mL, 0.84 mmol) was added to a solution of382-1 (0.10 g, 0.34 mmol),3-methoxy-4-(2-((methoxybenzyl)oxy)ethoxy)benzoic acid (0.15 g, 0.51mmol) and HATU (0.25 g, 0.67 mmol) in DMF (1 mL). The mixture wasstirred at r.t. for 2 h. The mixture was diluted with EA, and theorganic phase was washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel (EA:hexane) to give 382-2 (0.15 g, 76%). LCMS: m/z 581.15[M+H]⁺.

Compound 382-2 was deprotected in a similar manner as 368 to give 382-3LCMS: m/z 461.10 [M+H]⁺.

Cesium carbonate (0.11 g, 0.33 mmol) was added to a solution of 382-3(0.050 g, 0.11 mmol) and 2-(Boc-amino)ethyl bromide (0.048 g, 0.22 mmol)in DMF (1 mL). The mixture was heated under microwave irradiation at 70°C. for 1 h. The mixture was diluted with EA, and the organic phase waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 382-4 (39 mg, 60%). LCMS: m/z 604.20 [M+H]⁺.

Hydrochloric acid in dioxane (1.5 mL, 4N) was added to 382-4 (39 mg,0.077 mmol). The mixture was stirred at r.t. for 1 h and thenconcentrated under reduced pressure. The crude was purified by reversephase HPLC to give 382 (8 mg, 25%). LCMS: m/z 503.95 [M+H]⁺.

Example 184 Preparation of Compound 383

Compound 383-1 was prepared in a similar manner as 364 to give 383-2.LCMS: m/z 487.10 [M+H]⁺.

Dess-Martin periodinane (0.58 g, 1.4 mmol) was added to 383-2 (0.337 g,0.69 mmol) in CH₂Cl₂ (10 mL), and the mixture was stirred at r.t. for 1h. The mixture was diluted with CH₂Cl₂, washed with Na₂CO₃ and brine,dried over anhydrous Na₂SO₄ and concentrated. The crude was purified bychromatography on silica gel (EA:hexane) to provide 383-3 (0.144 g,43%). LCMS: m/z 485.10 [M+H]⁺.

Potassium tert-butoxide (40 mg, 0.36 mmol) was added totrimethylsulfoxonium iodide (65 mg, 0.30 mmol) in DMSO (1 mL), and themixture was stirred at r.t. for 30 mins. Compound 383-3 (0.144 g, 0.30mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h.The mixture was diluted with EA, and the organic phase was washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give383-4 (0.050 g, 33%). LCMS: m/z 499.15 [M+H]⁺.

Compound 383-4 (0.050 g, 0.10 mmol) was dissolved in 6N HCl (1 mL) andMeOH (1 mL) and heated at 60° C. for 2 h. The mixture was concentrated,and the crude was purified by reverse phase HPLC to give 383 (14 mg,28%). LCMS: m/z 517.10 [M+H]⁺.

Example 185 Preparation of Compound 384

Potassium tert-butoxide (81 mg, 0.72 mmol) was added totrimethylsulfoxonium iodide (0.13 g, 0.60 mmol) in DMSO (1 mL), and themixture was stirred at r.t. for 30 mins. Compound 384-1 (0.329 g, 0.60mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h.The mixture was diluted with EA, and the organic phase was washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give384-2 (0.11 g, 37%). LCMS: m/z 499.15 [M+H]⁺.

Compound 384-2 (0.11 g, 0.22 mmol) was dissolved in 6N HCl (1 mL) andMeOH (1 mL) and heated at 60° C. for 2 h. The mixture was concentratedand treated with 2N NaOH (2 mL) in MeOH (2 mL) for 2 h. The crude waspurified by reverse phase HPLC to give 384 (17 mg, 5%). LCMS: m/z 517.10[M+H]⁺.

Example 186 Preparation of Compound 385

LDA (2 M in THF, 1.4 mL, 2.8 mmol) was added dropwise to a solution of385-1 (0.93 g, 2.5 mmol) in THF (10 mL) at −78° C., and the mixture wasstirred at −78° C. for 15 mins. N-fluorobenzenesulfonimide (1.2 g, 3.8mmol) was added, and the mixture was stirred for 3 h. The mixture waswarmed to r.t., and the reaction was quenched with 1N HCl. The mixturewas extracted with EA, and the organic extracts were washed with brine,dried over sodium sulfate and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 385-2 (0.57 g, 59%).LCMS: m/z 386.10 [M+H]⁺.

Sodium borohydride (0.12 g, 3.1 mmol) was added to a solution of 385-2(0.14 g, 0.36 mmol) in EtOH. The mixture was stirred at r.t. for 2 h.The reaction was quenched with 1N HCl and extracted with EA. The organicextracts were washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 385-3 (0.040 g, 33%). LCMS: m/z 330.00 [M+H]⁺.

Compound 385-3 (25 mg, 0.076 mmol) in THF (1 mL) was added to NaH (3.0mg, 0.076 mmol) in THF (0.5 mL), and the mixture solution was stirredfor 30 mins. TBDMSCl (11 mg, 0.076 mmol) was added, and the mixture wasstirred at r.t. for 2 h. The reaction was quenched with 1N HCl andextracted with EA. The organic extracts were washed with brine, driedover sodium sulfate and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 385-4 (0.014 g, 41%).LCMS: m/z 444.10 [M+H]⁺.

Triflic anhydride (45 uL, 0.27 mmol) was added to a solution of 385-4(60 mg, 0.14 mmol) and 2,6-lutidine (47 uL, 0.40 mmol) in CH₂Cl₂ (1 mL)at −78° C. The mixture was warmed to r.t. The reaction was quenched with1N HCl and extracted with EA. The organic extracts were washed withbrine, dried over sodium sulfate and concentrated. The crude triflatewas immediately dissolved in NMP (0.5 mL) and tetrabutylammonium azide(0.39 g, 1.4 mmol) was added, and the mixture was heated at 65° C. for 1h. The mixture was diluted with EA, and organic extracts were washedwith water and brine, dried over sodium sulfate and concentrated. Thecrude was purified by chromatography on silica gel (EA:hexane) to give385-5 (0.057 g, 114%). LCMS: m/z 355.05 [M+H]⁺.

Compound 385-5 was reduced in a similar manner as 364 to give 385-6.LC/MS: [M+H] 329.00. Diisopropylethylamine (62 uL, 0.36 mmol) was addedto a solution of 385-6 (54 mg, 0.12 mmol),4-cyclopropoxy-3-methoxybenzoic acid (37 mg, 0.18 mmol) and HBTU (81 mg,0.21 mmol) in DMF (1 mL), and the mixture was stirred at r.t. for 1 h.The mixture was diluted with EA and washed with 1 N HCl, sodiumbicarbonate, water and brine, dried over sodium sulfate andconcentrated. The crude was purified by reverse phase HPLC to give 385(14 mg, 22%). LCMS: m/z 520.15 [M+H]⁺.

Example 187 Preparation of Compound 386

Methyl magnesium bromide (1.4 M in THF, 6.0 mL, 8.4 mmol) was added to asolution of ethyl 2,6-dichloroisonicotinate (0.74 g, 3.4 mmol) in THF(20 mL) at 0° C. The mixture was stirred at r.t. for 2 h. The reactionwas quenched with 1N HCl and extracted with EA. The organic extractswere washed with brine, dried over sodium sulfate and concentrated. Thecrude was purified by chromatography on silica gel (EA:hexane) to give386-2 (0.63 g, 88%). LCMS: m/z 206.00 [M+H]⁺.

TBDMSOTf (2.6 mL, 12 mmol) was added dropwise to a solution of 386-2(0.80 g, 3.9 mmol) and 2,6-lutidine (2.3 mL, 19 mmol) in CH₂Cl₂ (20 mL),and the mixture was stirred at r.t. for 3 h. The reaction was quenchedwith 1N HCl and extracted with EA. The organic extracts were washed withbrine, dried over sodium sulfate and concentrated. The crude waspurified by chromatography on silica gel (EA:hexane) to give 386-3 (1.2g, 96%). LCMS: m/z 320.05 [M+H]⁺.

Compounds 386-4, 386-5, 386-6, 386-7 and 386-8 were prepared in asimilar manner as 377. 386-4: LCMS: m/z 350.10 [M+H]⁺. 386-5: LCMS: m/z474.15 [M+H]⁺. 386-6: LCMS: m/z 607.20 [M+H]⁺. 386-7: LCMS: m/z 507.15[M+H]⁺. 386-8: LCMS: m/z 697.25 [M+H]⁺.

TBAF (1M in THF, 0.13 mL, 0.13 mmol) was added to a solution of 386-8(25, mg, 0.043 mmol), and the mixture was stirred at r.t. for 1 h. Themixture was concentrated, and 386 was purified by reverse phase HPLC (5mg, 20%). LCMS: m/z 583.20 [M+H]⁺.

Example 188 Preparation of Compound 387

Compound 314 (10 mg, 0.021 mmol) was dissolved in CH₂Cl₂ (1 mL). Ethylisocyanate (10 uL, 0.12 mmol) was added, and the mixture was stirred atr.t. for 5 h. The reaction was quenched with methanol (2 mL) andconcentrated. Compound 314 was purified by HPLC (4.1 mg, 40%). LCMS: m/z653.20 [M+H]⁺.

Example 189 Preparation of Compound 388

Sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added to a solutionof 318 (28 mg, 0.051 mmol) and acetaldehyde (9 uL, 0.16 mmol) in CH₂Cl₂(1 mL). Additional acetaldehyde and reducing agent were added every 30mins for 5 h. The reaction was quenched with ammonium chloride andextracted with CH₂Cl₂. Compound 388 was purified by reverse phase HPLC(14 mg, 50%) LCMS: m/z 576.20 [M+H]⁺.

Example 190 Preparation of Compound 393

NaH (9 mg, 0.22 mmol) was added to a solution of 393-1 (72 mg, 0.15mmol) in DMF (1 mL) and stirred for 15 mins. Iodomethane (18 uL, 0.29mmol) was added, and the mixture was stirred at r.t. for 3 h. Thereaction was quenched with sat. NH₄Cl and extracted with EA. Thecombined organic extracts were washed with water and brine, dried oversodium sulfate and concentrated. The crude was purified bychromatography on silica gel (EA:hexane) to give 393-2 (51 mg, 66%).LCMS: m/z 507.10 [M+H]⁺.

Potassium osmate (6 mg, 0.015 mmol) was added to a solution of 393-2 (51mg, 0.10 mmol) and tert-butyl (tosyloxy)carbamate (41 mg, 0.15 mmol) int-butanol (1 mL) and water (0.33 mL), and the solution was stirredovernight at r.t. The crude was purified by chromatography on silica gel(EA:hexane) to give 393-3 (0.025 g, 50%). LCMS: m/z 640.20 [M+H]⁺.

HCl (4N in dioxane, 1 mL) was added to 393-3 (0.025 g, 0.039 mmol), andthe mixture was stirred for 1 h. The solvent was removed by evaporationand 4-cyclopropoxy-3-methoxybenzoic acid (24 mg, 0.12 mmol), HATU (60mg, 0.16 mmol), and diisopropylethylamine (40 uL, 0.23 mmol) were added,and the mixture was stirred at r.t. for 1.5 h. The crude was dilutedwith EA and washed with 1N HCl, sodium bicarbonate and brine, dried oversodium sulfate and concentrated. The crude was purified by reverse phaseHPLC to provide 393-4 (12 mg, 41%). LCMS: m/z 730.15 [M+H]⁺.

Pd/C (10%, 3 mg) was added to a solution of 393-4 (12 mg, 0.025 mmol) inEtOH (3 mL), and the mixture was stirred under hydrogen atmosphere for 2h. The catalyst was removed by filtration, and the crude was purified byreverse phase HPLC to provide 393 (2.5 mg, 28%) LCMS: m/z 563.20 [M+H]⁺.

Example 191 Preparation of Compound 394

Sodium iodide (40 mg, 0.27 mmol) was added to a solution of 393-4 (40mg, 0.55 mmol) and chlorotrimethylsilane (35 uL, 0.27 mmol) inacetonitrile (3 mL), and the mixture was stirred at r.t. for 2 h. Thereaction mixture was diluted with EA and washed with sat. Na₂(SO₂)₃, andbrine, dried over Na₂SO₄ and concentrated. The product was purified byreverse phase HPLC to provide 394. LCMS: m/z 597.15 [M+H]⁺.

Example 192 Preparation of Compound 395

Compound 395-2 was prepared in a similar manner as 364. LCMS: m/z 706.20[M+H]⁺. Compound 395 was prepared in a similar manner as 396. LCMS: m/z607.10 [M+H]⁺.

Example 193 Preparation of Compound 396

Compound 396-2 was prepared in a similar manner as 364. LC/MS: m/z714.20 [M+H]. HCl (4N in dioxane, 2 mL) was added to 396-2 (80 mg, 0.11mmol) and the mixture was stirred for 2 h. The mixture was concentratedto remove volatile components, and 396 was purified by reverse phaseHPLC (11 mg, 15%). LCMS: m/z 615.15 [M+H]⁺.

Example 194 Preparation of Compound 397

Methanesulfonyl chloride (0.30 mL, 4.0 mmol) was added dropwise to asolution of 397-1 (0.70 g, 2.7 mmol) and diisopropylethylamine (0.93 mL,5.3 mmol) in CH₂Cl₂ (30 mL) at 0° C. for 30 mins. The mixture was washedwith 1N HCl, and brine, dried over Na₂SO₄ and concentrated. The crudewas purified by silica gel chromatography (EA:hexane) to provide 397-2(0.59 g, 85%). LCMS: m/z 349.95 [M+H]⁺.

Sodium cyanide (0.14 g, 2.8 mmol) was added to a solution of 397-2 (0.59g, 2.3 mmol) in ethanol (10 mL) and water (2 mL). The mixture was heatedat 50° C. for 30 mins. The mixture was diluted with EA and washed withwater and brine, dried over Na₂SO₄ and concentrated. The crude waspurified by silica gel chromatography (EA:hexane) to provide 397-3 (0.15g, 23%). LCMS: m/z 280.95 [M+H]⁺.

NaH (65 mg, 1.6 mmol) was added to a solution of 397-3 (0.15 g, 0.54mmol) in DMF (1 mL) and stirred for 5 mins. Iodomethane (0.16 mL, 3.0mmol) was added dropwise, and the mixture was stirred at r.t. for 1 h.The reaction was quenched with NH₄Cl and extracted with EA. The organicextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated. The crude was purified by silica gel chromatography(eluent: EA:hexane) to provide 397-4 (0.123 g, 72%). LCMS: m/z 308.95[M+H]⁺.

Borane-dimethylsulfide (0.11 mL, 0.11 mmol) was added dropwise to asolution of 397-4 (0.123 g, 3.9 mmol) in THF (2 mL), and the mixture washeated at 55° C. for 1 h. The reaction was quenched with 6N HCl andheated at 55° C. for 15 mins. The volatile components were removed byevaporation, and 397-5 was used without further purification. LCMS: m/z313.00 [M+H]⁺.

Benzyl chloroformate (85 uL, 0.59 mmol) was added dropwise to a solutionof 397-5 (3.9 mmol) and diisopropylethylamine (0.20 mL, 1.2 mmol) inCH₂Cl₂ (2 mL), and the mixture was stirred at r.t. for 1 h. The mixturewas diluted with EA and washed with water and brine, dried over Na₂SO₄and concentrated. The crude was purified by silica gel chromatography(EA:hexane) to provide 397-6 (0.15 g, 87%). LCMS: m/z 447.05 [M+H]⁺.

Compound 397-7 was prepared in a similar manner as 364. LCMS: m/z 507.10[M+H]⁺. Compound 397-8 was prepared in a similar manner as 377. LCMS:m/z 640.15 [M+H]⁺. Compound 397-9 was prepared in a similar manner as377. LCMS: m/z 730.15 [M+H]⁺. Compound 397 was prepared in a similarmanner as 394. LCMS: m/z 597.20 [M+H]⁺.

Example 195 Preparation of Compounds 366, 367, 370, 373, 376, 389, 390,391 and 392

TABLE 7 Example Method Structure LCMS: m/z Compound 365

533.10 [M + H]⁺ Compound 424

500.1 [M + H]⁺ Compound 369

555.10 [M + H]⁺ Compound 364

579.05 [M + H]⁺ Compound 364

515.05 [M + H]⁺ Compound 388

548.20 [M + H]⁺ Compound 388

611.10 [M + H]⁺ Compound 388

628.20 [M + H]⁺ Compound 388

625.15 [M + H]⁺

Example 196 Preparation of Compounds 246 and 247

Compound 370 (270 mg, 0.49 mmol) was separated via SFC to give twoenantiomers: 246 (100 mg, 74.0%) and 247 (110 mg, 81.5%). 246: +ESI-MS:m/z 555.1 [M+H]⁺. 247: +ESI-MS: m/z 555.1 [M+H]⁺.

Example 197 Preparation of Compound 398

To a stirring mixture of 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid(70 mg, 0.31 mmol) in DMF (1.5 mL) were added HATU (90 mg, 0.237 mmol)and DIPEA (84 μL, 0.474 mmol). The mixture was stirred at r.t. for 10mins.2-amino-1-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-1-cyclopropylethan-1-olin DMF (0.5 mL) as added. The mixture was stirred at for 10 mins, andthen quenched with a 10% aq. solution of NaHCO₃ (10 mL). The mixture wasdiluted with DCM, and a normal aqueous work up with DCM was followed.The crude was purified via prep-HPLC to afford 398 as a white solid.LCMS: m/z 544.15 [M+H]⁺.

Example 198 Preparation of Compound 399

Compound 399 was prepared in a manner similar to 398. LCMS: m/z 716.2[M+H]⁺.

Example 199 Preparation of Compound 400

To a stirring mixture of 400-1 (50 mg, 0.088 mmol, obtained during thepreparation of 314) in DMF (2.0 mL) were added Cs₂CO₃ (143 mg. 0.44mmol) and MeI (38 mg. 0.264 mmol). The mixture was stirred at r.t. untilthe starting material was consumed. The crude was diluted EtOAc andwater. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄,filtered and concentrated under reduced pressure. Compound 400 waspurified via HPLC to afford 400 as a white solid. LCMS: m/z 610.15[M+H]⁺.

Example 200 Preparation of Compound 401

To a stirring mixture of 401-1 (460 mg, 1.6 mmol) in DMF (2.5 mL,deoxygenated) were added PdCl₂(PPh₃)₂ (32 mg, 0.045 mmol), CuI (26 mg,0.136 mmol), piperidine (0.35 mL) and trimethyl(prop-2-yn-1-yl)silane(180 mg, 1.6 mmol). The mixture subjected to microwave irradiation at60° C. for 3 h. The mixture was cooled to r.t. and diluted with EtOAc.The mixture was washed with brine, water and NaHCO₃. The mixture wasdried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude was purified via a silica gel column to afford 401-2 as a yellowsolid. LCMS: m/z 198.05 [M+H]⁺.

To a stirring mixture of 401-2 (110 mg, 0.56 mmol) in DME (3 mL,deoxygenated) were added (3-chloro-4-fluorophenyl)boronic acid (191 mg,1.1 mmol), PdCl₂(dppf)₂ and a solution of Cs₂CO₃ (0.6 mL, 3.7 M). Themixture subjected to under microwave irradiation at 110° C. for 4 h. Themixture was diluted with EtOAc and water. The aqueous layer wasextracted with EtOAc, dried over MgSO₄, filtered and concentrated underreduced pressure. The crude was purified via a silica gel column toafford 401-3 as a white solid. LCMS: m/z 292.0 [M+H]⁺.

Compound 401-6 was prepared in 3 steps using methods similar to thosefor preparing 302. LCMS: m/z 321.0 [M+H]⁺. Compound 401-6 was coupledwith 3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid followedby alcohol oxidation and deprotection to afford 401. LCMS: m/z 513.05[M+H]⁺.

Example 201 Preparation of Compound 402

Diisopropylethylamine (24 uL, 0.14 mmol) was added to a solution of402-1 (21 mg, 0.045 mmol), 3-methoxy-4-[(methylcarbamoyl)methoxy]benzoicacid (22 mg, 0.090 mmol) and HATU (38 mg, 0.099 mmol) in DMF (1 mL), andthe mixture was stirred at r.t. for 2 h. The mixture was diluted withEA, washed with 1N HCl, water and brine, dried over Na₂SO₄ andconcentrated. The crude was purified by reverse-phase HPLC to provide402 (7.5 mg). LCMS: m/z 586.05 [M+H]⁺.

Example 202 Preparation of Compounds 403, 404 and 405

To a solution of 403-1 (6.0 g, 32.97 mmol) and K₂CO₃ (9.12 g, 66.1 mmol)in DMF (50 mL) was added 2-bromoacetonitrile (4.98 g, 39.52 mmol)dropwise. The mixture was stirred at 80° C. for 4 h. The mixture wasdiluted with water, and extracted with EA (3×100 mL). The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated at low pressure. The residue was purified by columnchromatography on silica gel (5˜10% EA:PE) to give 402-2 as a colorlessoil (5.1 g, 70%).

To a solution of 402-2 (8.0 g, 36.2 mmol) in MeOH/H₂O (2:1, 90 mL) wasadded NaOH (2.9 g, 72.4 mmol), and the mixture stirred at 50° C. for 1h. The mixture was diluted with water and extracted with EA (2×50 mL).The aqueous layer was acidified to pH 4.0 using 2.0 M HCl solution. Theaqueous phase was extracted with EA (2×150 mL). The combined organiclayer was washed with brine, dried over sodium sulfate and concentratedat low pressure to give 403-3 (5.6 g, 70%).

To a solution of 403-3 (530 mg, 2.35 mmol) in DMF (15 mL) were addedDIPEA (590 mg, 7.04 mmol) and HATU (885 mg, 2.35 mmol), and the mixturewas stirred at r.t. for 30 mins. The mixture was treated with2-amino-1-(6-(3-bromo-4-fluorophenyl)-5-methoxypyridin-2-yl)ethanol(403-4, 800 mg, 2.35 mmol), and the mixture was stirred at r.t. for 2 h.The mixture was diluted with water, and extracted with EA (3×20 mL). Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated at low pressure. The residue waspurified by column chromatography on silica gel (PE:EA 1:1) to give403-5 (1.0 g, 77.5%). +ESI-MS: m/z 547.9 [M+H]⁺.

To a solution of 403-5 (600 mg, 1.10 mmol) in DCM (20 mL) was added DMP(948 mg, 2.2 mmol) in portions, and the mixture was stirred at r.t. for1 h. The mixture was washed with sat. Na₂S₂O₃ solution and brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedat low pressure. The residue was purified by chromatography to give403-6 as a white solid (400 mg, 66.7%). +ESI-MS: m/z 546.1 [M+H]⁺.

To a solution of 403-6 (400 mg, 0.73 mmol) in THF (20 mL) was addedCH₃MgBr (2.4 mL, 7.3 mmol) dropwise, and the mixture was stirred at r.t.for 30 mins. The reaction was quenched with water, and extracted with EA(3×30 mL). The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated at low pressure. The residue waspurified by prep-HPLC to give 403 (60 mg) as a white solid. +ESI-MS: m/z562.1 [M+H]⁺.

Compound 403 (˜45 mg) was separated via SFC separation to give twoisomers: 404 (10.0 mg) and 405 (12.5 mg). 404: +ESI-MS: m/z 562.1[M+H]⁺. 405: +ESI-MS: m/z 562.0 [M+H]⁺.

Example 203 Preparation of Compounds 406 and 407

To a solution of 406-1 (540 mg, 1.53 mmol) in THF (4 mL) was addedcyclopropylmagnesium bromide (4 mL, 0.5M in THF) dropwise at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction was quenched withwater, and extracted with EA (3×20 mL). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified by chromatography (PE:EA 10:1) togive 406-2 (400 mg, 70%).

Compound 406-2 (400 mg, 1.0 mmol) was treated with concentrated ammoniawater (10 mL) and ethanol (10 mL) in an autoclave. After sealing, themixture was heated to 80° C. for 10 h with stirring. The mixture wascooled to r.t., and diluted with EA (30 mL). The mixture was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated at low pressure togive 406-3, which was used without further purification. +ESI-MS: m/z337.1 [M+H]⁺.

Compound 406-6 was prepared essentially as described in the preparationof 403 by using 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 406-3. Thecrude was purified by column chromatography (EA:PE 1:1) to give 406-4 asa white solid (201 mg, 73%). +ESI-MS: m/z 533.1 [M+H]⁺. Compound 406-4was separated via SFC separation to give two isomers: 406 (60 mg) and407 (65 mg). 406: +ESI-MS: m/z 533.1 [M+H]+. 407: +ESI-MS: m/z 533.1[M+H]+.

Example 204 Preparation of Compounds 408 and 409

To a solution of 408-1 (560 mg, 0.2 mmol) in THF (4 mL) was added MeMgCl(1 mL, 3 M in Et₂O). The mixture was stirred at 0° C. for 1 h. Thereaction was quenched with CBr₄ (5 g) in THF (10 mL). The mixture wasdiluted with EA (50 mL). The solution was washed with brine, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by silical gel to give 408-2 (402 mg, 70%). +ESI-MS: m/z 577.1[M+H]⁺.

Under N₂ atmosphere, a 50 mL flask with a magnetic stirring bar wascharged with 208-3 (300 mg, 0.75 mmol), 408-2 (290 mg, 0.5 mmol),Pd(dppf)Cl₂ (8 mg, 1 mmol %), KF (180 mg, 3.0 mmol), and dioxane:H₂O (20mL:5 mL). The mixture was stirred for 10 h at 100° C. The mixture wascooled to r.t. and diluted with water (50 mL) and EA (50 mL). Theorganic layer was separated, and the aqueous phase was extracted with EA(2×20 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (PE:EA 10:1) to give408-3 as a solid (280 mg, 70%). +ESI-MS: m/z 774.5 [M+H]⁺.

To a solution of 408-3 (280 mg, 0.36 mmol) in dioxane (8 mL) wad addedconc.HCl (2 mL). The mixture was stirred at 80° C. for 1 h. The mixturewas cooled to r.t. and diluted with water (15 mL) and EA (20 mL). Theorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by prep-HPLC togive 408-4 (189 mg).

Compound 408-4 (189 mg) was separated via SFC separation to give twoenantiomers: 408 (60 mg) and 409 (65 mg). 408: +ESI-MS: m/z 524.1[M+H]⁺. 409: +ESI-MS: m/z 524.1 [M+H]⁺.

Example 205 Preparation of Compounds 410 and 411

Compound 410-3 was prepared essentially as described in the preparationof 403 by using 410-1 and 410-2. The crude was purified by columnchromatography on silica gel (PE:acetone 5:1) to give 410-3 (1.8 g,89%). +ESI-MS: m/z 628.1 [M+H]⁺.

Compound 410-4 was prepared essentially as described in the preparationof 403. Crude 410-4 was obtained (0.8 g, 52.3%). +ESI-MS: m/z 626.1[M+H]⁺. Compound 410-5 was prepared essentially as described in thepreparation of 403. Crude 410-5 was purified by column chromatography onsilica gel (PE:acetone 5:1) to give 410-5 (496 g, 51%). +ESI-MS: m/z642.1 [M+H]⁺. Compound 410-5 was prepared essentially as described inthe preparation of 403. Crude 410-6 was purified by prep-HPLC to give410-6 (302 mg, 70%). +ESI-MS: m/z 512.1 [M+H]⁺. Compound 410-5 wasseparated via SFC separation to give 410 (30 mg) and 411 (28 mg). 410:+ESI-MS: m/z 512.1 [M+H]⁺. 411: +ESI-MS: m/z 512.1 [M+H]⁺.

Example 206 Preparation of Compounds 412 and 413

Compounds 412 and 413 were prepared essentially as described in thepreparation of 403 by using 412-1 and ethynyl magnesium bromide. Theproduct was purified by prep-HPLC and SFC separation. 412 (30 mg) and413 (32 mg) were obtained as white solids. 412: +ESI-MS: m/z 516.9[M+H]⁺. 413: +ESI-MS: m/z 516.9 [M+H]⁺.

Example 207 Preparation of Compounds 414, 415 and 416

Racemic 414 was prepared essentially as described in the preparation of403 by using 412-1 and (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid.Compound 414 was obtained as a white solid (150 mg). Compound 414 wasseparated via SFC separation to give two enantiomers: 415 (35 mg) and416 (38 mg). 415: +ESI-MS: m/z 519.1 [M+H]⁺. 416: +ESI-MS: m/z 519.0[M+H]⁺.

Example 208 Preparation of Compounds 417 and 418

Compounds 417 and 418 were prepared essentially as described in thepreparation of 403 by using 412-1 and(S)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Compounds 417 (36 mg)and 418 (39 mg). 417: +ESI-MS: m/z 518.9 [M+H]⁺. 418: +ESI-MS: m/z 518.9[M+H]⁺.

Example 209 Preparation of Compounds 419, 420 and 421

To a solution of 419-1 (1.0 g, 2.32 mmol) in dioxane:H₂O (4:1, 20 mL)was added NaHCO₃ (584.6 mg, 6.96 mmol) in one portion and Boc₂O (657.5mg, 3.02 mmol) in portions. The mixture was stirred at r.t. for 2 h, andthen diluted with water (50 mL) and EA (50 mL). The aqueous phase wasextracted by EA (2×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuum.The residue was purified by column chromatography on silica gel (PE:EA4:1) to give 419-2 (1.2 g, 97%). +ESI-MS: m/z 532.3 [M+H]⁺.

To a solution of 419-2 (1.2 g, 2.26 mmol) in DCM (20 mL) was added DMP(1.95 g, 4.52 mmol) in portions. The mixture was stirred at r.t. for 1h. The reaction was quenched with sat. Na₂S03 solution (50 mL), andextracted with CH₂Cl₂ (3×50 mL). The combined organic phase was washedwith brine, dried over anhydrous sodium sulfate and concentrated at lowpressure. The residue was purified by chromatography to give 419-3 as awhite solid (1.0 g, 83.3%). +ESI-MS: m/z 530.3 [M+H]⁺.

To a solution of 419-3 (1.0 g, 1.89 mmol) in THF (15 mL) was addedCH₃MgBr (6.30 mL, 18.90 mmol) dropwise at 0° C., and the mixture wasstirred at r.t. for 30 mins. The reaction was quenched with water, andextracted with EA (3×30 mL). The combined organic phase was dried overanhydrous sodium sulfate and concentrated at low pressure. The crude waspurified by column chromatography (PE:EA 3:1˜2:1) to give 419-4 as awhite solid (605 mg, 58.3%). +ESI-MS: m/z 546.2 [M+H]⁺.

To a solution of 419-4 (600 mg, 1.1 mmol) in dioxane (16 mL) was addedcone. HCl (8 mL). The mixture was stirred at 80° C. overnight. Aftercooled to r.t., the mixture was neutralized by sat. NaHCO₃ solution, andextracted with EA (3×50 mL). The combined organic phase was washed withbrine, dried over anhydrous sodium sulfate and concentrated at lowpressure to give 419-5 (301 mg, 87%).

Compound 419 was prepared essentially as described in the preparation of403 by using 419-5 and 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid.Compound 491 was obtained as a white solid (90 mg). +ESI-MS: m/z 523.1[M+H]⁺.

Compound 419 (90 mg, 0.172 mmol) was separated via SFC separation togive two enantiomers: 420 (15.0 mg) and 421 (22.0 mg). 420: +ESI-MS: m/z523.1 [M+H]⁺. 421: +ESI-MS: m/z 523.1 [M+H]⁺.

Example 210 Preparation of Compounds 422 and 423

To a solution of 422-1 (100 mg, 0.575 mmol) in THF (10 mL) was NaBH₄ (44mg, 1.1 mmol) was added, and the mixture was stirred at r.t. for 30mins. The reaction was quenched by water, and extracted with EA (3×20mL). The organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated at low pressure. The crude was purified bychromatography (PE:EA 20:1 to 5:1) to afford 422-2 (90 mg, 89.1%).

To a solution of 422-2 (534 mg, 3.0 mmol), methyl4-hydroxy-3-methoxybenzoate (546 mg, 3.0 mmol) and PPh₃ (786 mg, 3.0mmol) in THF (15 mL) at 0° C. was added DIAD (606 mg, 3.0 mmol)dropwise. The mixture was stirred at r.t. for 2 h. The reaction wasquenched with sat. NaHCO₃ solution. The mixture was extracted with DCM(3×20 mL). The combined organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated at low pressure. The residuewas purified by flash column chromatography on silica gel to give 422-3(667 mg, 66%).

A solution of 422-3 (2.0 g, 5.85 mmol) and Pd(OH)₂ (0.2 g) in MeOH (20mL) was stirred under H₂ atmosphere (50 psi) at r.t. overnight. Themixture was filtered, and the filtrate was evaporated to give crude422-4 (1.5 g), which was used without further purification.

To a solution of 422-4 (150 mg, 0.597 mmol) in THF (10 mL) at 0° C. wasadded NaH (47.8 mg, 1.195 mmol), and the mixture was stirred at 0° C.for 0.5 h. The mixture was treated with SEMCl (149 mg, 0.896 mmol), andthe mixture was allowed to warm to r.t. over 30 mins. The reaction wasquenched with water, and extracted with EA (2×30 mL). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE:EA 20:1) to give 422-5 (110 mg, 48.2%).

To a solution of 422-5 (600 mg, 1.57 mmol) in co-solvent THF:H₂O (1:1,10 mL) was added NaOH (126 mg, 3.14 mmol in 2 mL water). The mixture wasstirred at r.t. for 1 h. The organic solvent was evaporated underreduced pressure, and the aqueous layer was acidified to pH 4˜5 with 1MHCl solution. The mixture was extracted with EA (2×20 mL). The combinedorganic phase was dried over anhydrous sodium sulfate and concentratedat low pressure to give 422-6 (480 mg, 83.0%).

Compound 422-8 was prepared essentially as described in the preparationof 403 by using 422-6 and 422-7. Compound 422-8 was obtained as a whitesolid (180 mg, 66.9%). +ESI-MS: m/z 661.0 [M+H]⁺.

A suspension of 422-8 (180 mg, 0.273 mmol) in HCl:dioxane (4M, 15 mL)was stirred at r.t. for 30 mins. The mixture was concentrated underreduced pressure to give crude 422-9. The residue was diluted with sat.NaHCO₃ (10 mL), and extracted with EA (2×10 mL). The combined organicphase was washed with brine, dried over anhydrous sodium sulfate andconcentrated at low pressure. The residue was purified by columnchromatography on silica gel (PE:EA 5:1 to 1:1) to give 422-9 (90 mg,62.3%).

Compound 422-9 (90 mg) was separated by SFC separation to give twoenantiomers: 422 (25 mg) and 423 (27 mg). 422: +ESI-MS: m/z 531.0[M+H]⁺. 423: +ESI-MS: m/z 531.0 [M+H]⁺.

Example 211 Preparation of Compound 424

To a solution of 424-1 (1.05 g, 3.0 mmol) and 18-crowm-6 (800 mg, 3.1mmol) in CH₃CN (50 mL) was added CsF (900 mg, 6.0 mmol). The mixture washeated to reflux for 1 h and the concentrated under reduced pressure.The residue was purified by column chromatography (PE:EA 10:1) toprovide 424-2 as a white solid (360 mg, 40%).

A 50 mL round bottom flask with a magnetic stirring bar was charged with424-2 (360 mg, 1.2 mmol), MeNO₃ (5 mL) and Et₃N (303 mg, 3.0 mmol). Themixture was stirred at r.t. for 10 h and then concentrated under reducedpressure. The residue was purified by column chromatography (PE:DCM 2:1)to give 424-3 (270 mg, 63%).

To a stirred mixture of 424-3 (271 mg, 0.75 mmol) and NiCl₂ (127 mg, 1mmol) in MeOH (10 mL) was added NaBH₄ (380 mg, 1.0 mmol) in portionsuntil the starting materials was consumed. The mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography (EA:EtOH 10:1) to give 424-4 as a colorless oil (130 mg,50%). +ESI-MS: m/z 328.8 [M+H]⁺.

Compound 424 was prepared essentially as described in the preparation of403 by using the 424-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid.The product was purified by prep-HPLC. Compound 424 was obtained as awhite solid (180 mg, 66.9%). +ESI-MS: m/z 523.2 [M+H]⁺.

Example 212 Preparation of Compound 425

Compound 425-3 was prepared essentially as described in the preparationof 403 by using 425-1 and 425-2. The crude was purified by columnchromatography (PE:EA 1:1) to give 425-3 (190 mg). +ESI-MS: m/z 654.9[M+H]⁺.

To a solution of 425-3 (190 mg, 0.29 mmol) in dioxane (15 mL) was addedcone. HCl (5.0 mL). The mixture was stirred at r.t. for 1 h, neutralizedwith sat. NaHCO₃ solution and extracted with EA (3×10 mL). The organiclayer was dried over anhydrous sodium sulfate, and concentrated at lowpressure. The residue was purified by prep-HPLC to give 425 (21 mg,13.5%) as a white solid. +ESI-MS: m/z 534.9 [M+H]⁺.

Example 213 Preparation of Compound 426

To a stirred solution of 426-1 (16.2 g, 90 mmol) in HCl (6 N, 300 mL) at0° C. was added a solution of NaNO₂ (6.90 g, 99 mmol) in water (15 mL)dropwise. The mixture was stirred at 0° C. for 1 h and then treated witha solution of KI (75 g, 450 mmol) in water (150 mL). The mixture wasstirred for 30 mins and then extracted with EA (4×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedat low pressure. The residue was purified by column chromatography(PE:EA 10:1) to give 426-2 (21.2 g, 80.5%) as a light yellow solid.

To a suspension of 426-2 (8.77 g, 30 mmol), CuI (1.14 g, 6 mmol),PdCl₂(PPh₃)₂ (1.05 g, 1.5 mmol) and NEt₃ (21 mL, 150 mmol) in THF (150mL) was added propiolic alcohol (3.36 g, 60 mmol) under N₂ atmosphere.The mixture was stirred at r.t. overnight and then filtered through acelite pad. The filtrate was concentrated to dryness and the residue wasdiluted with EA (200 mL). The solution was washed with brine, dried overanhydrous sodium sulfate and concentrated at low pressure. The residuewas purified by column chromatography on silica gel (PE:EA 1:1) to give426-3 (5.1 g, 77.3%) as a light yellow solid.

To a solution of 426-3 (2.2 g, 10 mmol) in MeOH (100 mL) was added Pd/C(0.5 g) under N2. The mixture was degassed and refilled with hydrogen(3×). The mixture was stirred under H₂ atmosphere (40 psi) overnight.The mixture was filtered through a celite pad and the filtrate wasconcentrated in vacuum to give crude 426-4. The residue was purified bycolumn chromatography on silica gel (PE:EA 1:1) to give 426-4 (1.62 g,72.3%) as a light yellow oil.

To a solution of 426-4 (0.67 g, 3 mmol) in EtOH (7.5 mL) and water (2.5mL) was added NaOH (0.48 g, 12 mmol). The mixture was stirred at 50° C.for 1 h, cooled to 0° C., and acidified to pH 5 with HCl (2 M) solution.The mixture was extracted with EA (4×50 mL). The combined organic layerwas dried over anhydrous sodium sulfate and concentrated in vacuum togive 426-5 (0.50 g, 80.0%) as a yellow solid, which was used withoutfurther purification.

Compound 426 was prepared essentially as described in the preparation of403 by using 426-5 and2-amino-1-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-1-cyclopropylethanol.The crude was purified by prep-HPLC to give 426 (35 mg, 13.3%) as awhite solid. +ESI-MS: m/z 529.0 [M+H]⁺.

Example 214 Preparation of Compound 427

To a suspension of 427-1 (1.0 g, 4.67 mmol) in dioxane (30 mL) wereadded 427-2 (2.37 g, 9.346 mmol), AcOK (1.37 g, 14.0 mmol) andPd(dppf)Cl₂ (0.346 g, 0.467 mmol). The mixture was stirred at 80° C.under N₂ atmosphere for 16 h. The mixture was cooled to r.t., pouredinto water (100 mL), and extracted with DCM (3×50 mL). The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated at low pressure. The residue was purified by columnchromatography (PE:EA 50:1) to give 427-3 (1.4 g, contain 0.3-0.4 g of427-2).

To a solution of 427-4 (310 mg, 0.554 mmol) in THF (10 mL) at 0° C. wasadded cyclopropyl-magnesium bromide (11 mL, 0.5 M in THF) dropwise. Themixture was stirred for 1 h and then warmed to r.t. The reaction wasquenched with sat. NH₄Cl (10 mL) solution, and extracted with EA (2×20mL). The combined organic phase was washed with sat. NaHCO₃ solution,and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by columnchromatography on silica gel (30% EA in PE) to give 427-5 (170 mg,51.0%). +ESI-MS: m/z 601.1 [M+H]⁺.

To a suspension of 427-5 (120 mg, 0.2 mmol) in a mixture of dioxane andH₂O (9:1, 10 mL) were added Cs₂CO₃ (195.6 mg, 0.6 mmol), 427-3 (108.6mg, 0.3 mmol) and Pd(dppf)Cl₂ (16.3 mg, 0.02 mmol) under N₂ atmosphere.The mixture was stirred at 70° C. for 2 h. The mixture was cooled tor.t., poured into water (50 mL) and extracted with EA (2×50 mL). Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated at low pressure. The residue was purified bycolumn chromatography (10-30% EA in PE) to give 427-6 (121 mg, 92.2%).+ESI-MS: m/z 657.1 [M+H]⁺.

A suspension of 427-6 (121 mg, 0.184 mmol) and Pd/C (20 mg) in MeOH (20mL) was stirred under H₂ atmosphere (balloon) at r.t. overnight. Thesolution was filtered, and the filtrate was concentrated in vacuum. Theresidue was purified by prep-HPLC to give 427 (17 mg, 10.1%) as a whitesolid. +ESI-MS: m/z 539.1 [M+H]⁺.

Example 215 Preparation of Compound 428

Compound 428-2 was prepared as provided in Mello et al., J. Am. Chem.Soc. (2005) 127(29): 10124-10125, which is hereby incorporated byreference for the limited purpose of its description of the preparationof 428-2. Compound 428-3 was prepared as provided in PCT Publication No.WO 2002/034745, published May 2, 2002, which is hereby incorporated byreference for the limited purpose of its description of the preparationof 428-3.

To a solution of 428-3 (8 g, 38 mmol) in DMF (100 mL) were added K₂CO₃(9.5 g, 69 mmol) and NaN₃ (3 g, 46 mmol) at r.t. The solution wasstirred for 2 h, poured into H₂O (100 mL) and extracted with EA (3×100mL). The combined organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated at low pressure. The residuewas purified by column chromatography (PE:EA 10:1) to give 428-4 (5.1 g,66.1%).

To a solution of 428-4 (5 g, 23.4 mmol) in EtOH (50 mL) were added Boc₂O(6.11 g, 28 mmol) and Pd/C (1 g) at r.t. under N2. The solution wasdegassed and refilled with Eh (3×). The mixture was stirred at r.t.under Eh atmosphere (balloon) for 18 h. The solution was filtered, andthe filtrate was concentrated to dryness. The residue was purified bychromatography on silica gel (PE:EA 10:1) to give 428-5 (2.2 g, 34.4%).

To a solution of 428-5 (2.2 g, 7.9 mmol) and(3-chloro-4-fluorophenyl)boronic acid (1.39 g, 7.9 mmol) in a mixture ofdioxane and H₂O (20 mL/5 mL) were added Pd(dppf)Cl₂ (289 g, 0.395 mmol)and K₂CO₃ (1.63 g, 11.85 mmol). The mixture was degassed and refilledwith N2 (3×). The mixture was stirred under N2 at 40° C. for 3 h. Themixture was cooled to r.t., and diluted with EA (100 mL) and water (100mL). The organic phase was washed with brine, dried over anhydroussodium sulfate and concentrated at low pressure. The residue waspurified by column chromatography on silica gel (PE:EA 10:1) to give428-6 (2.923 g, 100%) as a white solid. +ESI-MS: m/z 370.8 [M+H]⁺.

To a solution of 428-6 (1.2 g, 3.24 mmol),tributyl(1-ethoxyvinyl)stannane (2.34 g, 6.48 mmol) and KF (751 mg,12.96 mmol) in DMF (15 mL) was added Pd(dppf)Cl₂ (237 mg, 0.324 mmol)under N2. The mixture was stirred at 80° C. for 2 h. After cooling tor.t., the mixture was diluted with EA (100 mL) and water (50 mL). Theorganic phase was washed with brine, dried over anhydrous sodium sulfateand concentrated at low pressure to give crude 428-7 (1.35 g crude),which was used in the next step directly. +ESI-MS: m/z 407.1 [M+H]⁺.

Compound 428-7 (1.315 g, 3.24 mmol) was dissolved in THF (20 mL) and H₂O(2 mL). The solution was treated with NBS (1.13 g, 6.4 mmol) at r.t.,and stirred for 20 mins. The mixture was concentrated at low pressure,and the residue was purified by column chromatography on silica gel(PE:EA 10:1) to give 428-8 (1.4 g, 94.5%). +ESI-MS: m/z 459.1 [M+H]⁺.

Compound 428-9 was prepared essentially as described in the preparationof 406 by using 428-8. Crude 428-9 (410 mg, 63%) was used directly inthe next step. Compound 428-10 was prepared essentially as described inthe preparation of 406 by using crude 428-9. Crude 428-10 (205 mg,57.6%) was used directly in the next step. +ESI-MS: m/z 436.3 [M+H]⁺.Compound 428-11 was prepared essentially as described in the preparationof 406 by using crude 428-10 and3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid. Crude 428-11was purified by column chromatography on silica gel (50% EA in PE) togive purified 428-11 (106 mg, 30.1%).

To a solution of 428-11 (100 mg, 0.13 mmol) in dioxane (2 mL) was addedcone. HCl (2 mL) at r.t., and the mixture was stirred for 30 mins. Themixture was neutralized using a sat. Na₂CO₃ solution, and extracted withEA (3×10 mL). The combined organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by prep-HPLC to give 428 (15 mg, 21.2%) as a white solid.+ESI-MS: m/z 530.0 [M+H]⁺.

Example 216 Preparation of Compounds 429, 430 and 431

Compound 429 was prepared essentially as described in the preparation of403 by using 403-3 and 406-3. Compound 429 was obtained as a white solid(50 mg). +ESI-MS: m/z 544.1 [M+H]⁺.

Compound 429 was separated via SFC separation to give two enantiomers:430 (3.22 mg, 12.9%) and 431 (3.45 mg, 13.8%). 430: +ESI-MS: m/z 544.1[M+H]⁺. 431: +ESI-MS: m/z 544.1 [M+H]⁺.

Example 217 Preparation of Compound 432

To a solution of 432-1 (2.0 g, 10.99 mmol) in DMF (20 mL) were addedClCF₂COONa (3.0 g, 19.74 mmol) and K₂CO₃ (4.4 g, 31.88 mmol). Themixture was stirred at 95° C. for 5 h. After cooling to r.t., themixture was poured into water (100 mL) and extracted with EA (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated at low pressure. The residue waspurified by column chromatography on silica gel (5-20% EA in PE) to give432-2 (1.3 g, 51.0%).

Compound 432-3 was prepared essentially as described in the preparationof 426 using 432-2. Compound 432-3 was obtained as a white solid (1.19g, 97.5%). Compound 432 was prepared essentially as described in thepreparation of 406 by using 432-3 and 432-4. Compound 432 was obtainedafter purification by prep-HPLC as a white solid (70 mg, 21.7%).+ESI-MS: m/z 537.1 [M+H]⁺.

Example 218 Preparation of Compound 433

To a solution of 433-1 (2 g, 6.8 mmol), potassium trifluoro(vinyl)borate(0.917 mg, 6.8 mmol) and Et₃N (1.73 g, 17.12 mmol) in MeOH (30 mL) wasadded Pd(dppf)Cl₂ (497 mg, 0.68 mmol) under N2. The mixture was stirredunder N2 at 70° C. for 15 h. The solution was cooled to r.t., anddiluted with EA (100 mL) and water (50 mL). The organic phase was washedwith brine, dried over anhydrous sodium sulfate and concentrated at lowpressure. The residue was purified by column chromatography on silicagel (3% EA in PE) to give 433-2 as a colorless oil (1.1 g, 84.6%).

To a solution of 433-2 (730 mg, 3.84 mmol) in THF (15 mL) was addedBEE.THF (4 mL, 1 M) at 0° C., and the reaction was stirred at 0° C. for1 h. The solution was treated with NaOH (10 mL, 1 M in water) and H₂O₂(3 mL) at 0° C. The mixture was stirred at r.t. for 1 h, and extractedwith EA (3×30 mL). The combined organic phase was washed with brine,dried over anhydrous sodium sulfate and concentrated at low pressure.The residue was purified by column chromatography (PE:EA 5:1) to give433-3 (320 mg. 40.4%).

Compound 433-4 was prepared essentially as described in the preparationof 426 using 433-3. Compound 433-4 obtained as a white solid (210 mg,70.7%). Compound 433 was prepared essentially as described in thepreparation of 406 by using 433-4 and 433-5. Compound 433 was obtainedafter purification by prep-HPLC as a white solid (32 mg, 8.2%). +ESI-MS:m/z 515.0 [M+H]⁺.

Example 219 Preparation of Compound 434

Compound 434-2 was prepared as described in PCT Publication No. WO2009/055077, published on Apr. 30, 2009, which is hereby incorporated byreference for the limited purpose of its description of the preparationof 434-2.

To a suspension of 1, 2, 4-triazole (0.52 g, 7.51 mmol), and K2CO₃ (2.57g, 20.49 mmol) in DMF (15 mL) was added 434-2 (1.77 g, 6.83 mmol) at 0°C., and stirred at r.t. overnight. The mixture was poured into water(100 mL), and extracted by EA (4×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated at low pressure. The residue was purified by columnchromatography

Compound 434-4 was prepared essentially as described in the preparationof 426 by using 434-3. Compound 434-4 was obtained as a white solid (0.4g, 57.2%). Compound 434 was prepared essentially as described in thepreparation of 406 by using 434-4 and 434-5. Compound 434 was obtainedafter purification by prep-HPLC as a white solid (135 mg, 27.2%).+ESI-MS: m/z 552.1 [M+H]⁺.

Example 220 Preparation of Compound 435

To a solution of 435-1 (270 mg, 0.75 mmol) in DCM (10 mL) was added BAST(220 mg, 1.0 mmol) at r.t. The mixture was stirred at r.t. for 1 h. Thereaction was quenched with sat. NaHCO₃ solution (20 mL), extracted withEA (3×30 mL). The combined organic phase was washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.Crude 435-2 (271 mg, 99%) was used without further purification.

To a solution of 435-2 (271 mg, 0.75 mmol) and NiCl₂ (127 mg, 1 mmol) inMeOH (10 mL) was added NaBH₄ (380 mg, 1.0 mmol) in portions until thestarting materials was consumed. The reaction was quenched by water (10mL), and extracted with EA (3×30 mL). The organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (10% EtOH in EA) to give 435-3 as a colorless oil (130 mg, 50%).+ESI-MS: m/z 331.1 [M+H]⁺.

Compound 435 was prepared essentially as described in the preparation of406 by using 435-4 and 435-5. Compound 435 was obtained afterpurification by prep-HPLC as a white solid (85 mg, 47%). +ESI-MS: m/z525.2 [M+H]⁺.

Example 221 Preparation of Compound 436

To a stirred solution of 436-1 (800 mg, 2.02 mmol) and PhSO₂CHF₂ (465mg, 2.42 mmol) in THF (10 mL) was added LDA (2 mL, 4 mmol) dropwise at−78° C. under N₂ atmosphere. The mixture was stirred at −78° C. for 2 h,and warmed to 0° C. for 30 mins. The reaction was quenched with sat.NH₄Cl solution, and extracted with EA (3×30 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 3:1) to give 436-2 (610 mg, 51.6%). +ESI-MS: m/z587.1 [M+H]⁺.

To a solution of 436-2 (610 mg, 1.04 mmol) in DMF (5 mL) were added HOAc(1 mL) and H₂O (1 mL) at r.t. The mixture was treated with magnesium(250 mg, 10.4 mmol) in portions. After stirring at r.t. for 6 h, themixture was poured into ice-water (50 mL) and extracted with EA (3×30mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 436-3(320 mg, 68.9%). +ESI-MS: m/z 446.9 [M+H]⁺.

To a solution of 436-3 (320 mg, 0.72 mmol) in EA (3 mL) was added HCl/EA(3 mL, 4M). The solution was stirred at r.t. for 30 mins, and thenconcentrated to dryness. Crude 436-4 (220 mg, 90.9%) was used withoutpurification.

Compound 436 was prepared essentially as described in the preparation of406 by using 436-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid.Compound 436 was obtained after purification by prep-HPLC as white solid(40 mg, 11.7%). +ESI-MS: m/z 541.0 [M+H]⁺.

Example 222 Preparation of Compound 437

To a solution of 437-1 (1.0 g, 5.5 mmol) and K₂CO₃ (1.0 g, 7.3 mmol) ina mixture of CH₃CN (10 mL) and H₂O (2 mL) was added2-bromo-1,1-difluoroethene (10.0 mL, ˜2 M in acetonitrile) at 0° C. Themixture was stirred at 50° C. for 10 h. After cooling to r.t, themixture was poured into water (50 mL) and extracted with EA (3×30 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 10:1) to give 437-2 as an oil (0.4 gcrude).

To a solution of 437-2 (0.4 g, 1.2 mmol) in MeOH (20 mL) was added Pd/C(0.3 g) under N2. The suspension was degassed and refilled with H₂ (3×).The mixture was stirred under H₂ (50 psi) at r.t. for 5 h. Thesuspension was filtered through a Celite pad, and the filtrate wasconcentrated to dryness. The residue was purified by columnchromatography (PE:EA 9:1) to give 437-3 as a white solid (250 mg,84.7%).

Compound 437-4 was prepared essentially as described in the preparationof 426 by using 437-3. Compound 437-4 was obtained as a white solid (201mg, 85.1%). Compound 437 was prepared essentially as described in thepreparation of 406 by using 437-4 and 437-5. Compound 437 was obtainedafter purification by prep-HPLC as white solid (50 mg, 36.4%). +ESI-MS:m/z 551.2 [M+H]⁺.

Example 223 Preparation of Compound 438

Compound 438-1 was prepared in a similar manner as 434. Compound 438-4was prepared in a similar manner as 406. Compound 438 was preparedessentially as described in the preparation of 434 by using 438-3 and438-4. Compound 438 was obtained after purification by prep-HPLC aswhite solid (230 mg, 23%). +ESI-MS: m/z 551.0 [M+H]⁺.

Example 224 Preparation of Compound 439

To a solution of 439-6 (2.334 g, 6 mmol) in DMF (20 mL) were addedN,O-dimethyl-hydroxylamine hydrochloride (873 mg, 9 mmol), DIPEA (2.322g, 18 mmol) and HATU (3.42 g, 9 mmol), and the mixture was stirred atr.t. for 1 h. The mixture was poured into water (50 mL), and extractedwith EA (3×50 mL). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (20-50% EA in PE) to give439-7 (2.4 g, 92.7%). +ESI-MS: m/z 433.1 [M+H]⁺.

Compound 439-2 was prepared essentially as described in the preparationof 428 by using 439-1 and 3-chloro-4-fluorophenylboronic acid. Compound439-2 was obtained as a white solid (0.61 g, 69.0%). Compound 439-3 wasprepared essentially as described in the preparation of 426 by using439-2. Compound 439-3 was obtained as a white solid (0.97 g, 58.8%).

To a solution of 439-3 (1.6 g, 4.8 mmol) and 439-7 (2.1 g, 4.8 mmol) inanhydrous THF (20 mL) was added isopropyl-magnesium chloride (18.5 mL,24.1 mmol) dropwise at 0° C., and the mixture was stirred at r.t. for 1h. The mixture was quenched with water, and extracted with EA (2×50 mL).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (10-50% EA in PE) to give 439-4 (1.2 g, 64%).+ESI-MS: m/z 578.0 [M+H]⁺.

Compound 439-5 was prepared essentially as described in the preparationof 403 by using 439-4. Compound 439-5 was obtained as a white solid (160mg, 27.0%). +ESI-MS: m/z 594.0 [M+H]+. Compound 439 was preparedessentially as described in the preparation of 425 by using 439-5.Compound 439 was obtained as a white solid (101 mg, 79.2%). +ESI-MS: m/z473.8 [M+H]⁺.

Example 225 Preparation of Compound 440

Compound 440 was prepared essentially as described in the preparation of406 by using2-bromo-1-(6-(3-chloro-4-fluorophenyl)-4-ethylpyridin-2-yl)ethanone.Compound 440 was obtained as a white solid (197 mg, 73%). +ESI-MS: m/z523.1 [M+H]⁺.

Example 226 Preparation of Compound 441

Compound 441 was prepared essentially as described in the preparation of428 by using 2,4-dibromothiazole. Compound 441 was obtained as a whitesolid (60 mg, 35.7%). +ESI-MS: m/z 480.8 [M+H]⁺.

Example 227 Preparation of Compound 442

Compound 442-1 was prepared as essentially described in the preparationof 436. Compound 442-2 was prepared as essentially described in thepreparation of 403. Compound 442 was prepared essentially as describedin the preparation of 406 by using 442-1 and 442-2. Crude 442 waspurified by prep-HPLC to give 442 as a white solid (65 mg, 13.3%).+ESI-MS: m/z 554.1 [M+H]⁺.

Example 228 Preparation of Compound 443

To a solution of 443-1 (511 mg, 1.27 mmol) in anhydrous DMF (5 mL) wereadded TMS-CF₃ (217 mg, 1.53 mmol) and LiOAc (8.4 mg, 0.127 mmol) atr.t., and the mixture was stirred for 24 h. The mixture was treated withHCl (1.5 mL, 1 M) solution, and stirred at r.t. for 1 h. The mixture wasdiluted with water (20 mL), and extracted with EA (2×40 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatography (PE:EA 5:1) to give 443-2 (131 mg,21.8%).

Compound 443 was prepared essentially as described in the preparation of428 by using 443-2 and 442-2. Compound 443 was obtained as a white solid(92 mg, 53.2%). +ESI-MS: m/z 616.0 [M+H]⁺.

Example 229 Preparation of Compound 444

Compound 444 was prepared essentially as described in the preparation of406 by using 444-1 and 444-2. Compound 444 was purified by prep-HPLC togive 444 as a white solid (55 mg, 25.4%). +ESI-MS: m/z 555.0 [M+H]⁺.

Example 230 Preparation of Compound 445

Compound 445 was prepared essentially as described in the preparation of406 by using 445-1 and 445-2. Compound 445 was purified by prep-HPLC togive 445 as a white solid (56 mg, 36.3%). +ESI-MS: m/z 537.0 [M+H]⁺.

Example 231 Preparation of Compounds 446 and 447

Compound 442 (60 mg) was separated via SFC separation to give twoisomers: 446 (25 mg) and 447 (25 mg). 446: +ESI-MS: m/z 554.0 [M+H]⁺.447: +ESI-MS: m/z 554.1 [M+H]⁺.

Example 232 Preparation of Compound 448

Compound 448-2 was prepared essentially as described in Jang et al.,Tet. Lett. (2006) 47(50):8917-8920, which is hereby incorporated byreference for the limited purpose of its description of the preparationof 448-2. To a suspension of 448-2 (6.0 g, 22.9 mmol) and K₂CO₃ (6.3 g,45.6 mmol) in CH₃CN (40 mL) was added MeI (6.5 g, 45.6 mmol) at r.t. Thesolution was heated to 80° C. and stirred for 8 h. The precipitate wasremoved by filtration, and the organic layer was concentrated underreduced pressure. The residue was purified by column chromatography(PE:EA 20:1) to give 448-3 (5.5 g, 87.3%) as a white solid.

Compound 448 was prepared essentially as described in the preparation of428 and 443 by using 448-3 and 448-4. Crude 448 was purified byprep-HPLC to give 448 as a white solid (40 mg, 51.9%). +ESI-MS: m/z554.0 [M+H]⁺.

Example 233 Preparation of Compounds 449 and 450

Step 1 and step 3 were conducted as essentially as described in thepreparation of 232. Step 2 was conducted as essentially as described inthe preparation of 426. To a solution of 449-4 (1.0 g, 2.06 mmol) inAcOH (10 mL) was added Fe (576 mg, 10.3 mmol) powder in portions. Themixture was stirred at 80° C. for 2 h. After cooling to r.t, the mixturewas neutralized with sat. Na₂CO₃ solution, and extracted with EA (3×50mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column (PE:EA 3:1) to give 449-5 (435 mg, 46.4%).+ESI-MS: m/z 457.0 [M+H]⁺.

Compound 449-6 was prepared essentially as described in the preparationof 406 by using 449-5 and (R)-4-(2-hydroxypropoxy)-3-methoxybenzoicacid. Crude 449-6 was purified by prep-HPLC to give 449-6 (92 mg,40.4%). +ESI-MS: m/z 665.0 [M+H]⁺. Compound 449-6 (92 mg) was separatedvia SFC separation to give two isomers: 449 (32 mg) and 450 (33 mg).449: +ESI-MS: m/z 665.0 [M+H]⁺. 450: +ESI-MS: m/z 665.1 [M+H]⁺.

Example 234 Preparation of Compound 451

Compound 451 was prepared essentially as described in the preparation of443 and 448 by using 451-1. Crude 451 was purified by prep-HPLC to give451 as a white solid (42 mg, 16.0%). +ESI-MS: m/z 553.9 [M+H]⁺.

Example 235 Preparation of Compound 452

Compound 452-1 was prepared essentially as described in the preparationof 259. Compound 452-2 was prepared essentially as described in thepreparation of 471. Compound 452 was prepared essentially as describedin the preparation of 406 by using 452-1 and 452-2. Crude 452 waspurified by prep-HPLC to give 452 as a white solid (90 mg, 19%).+ESI-MS: m/z 564.0 [M+H]⁺.

Example 236 Preparation of Compound 453

To a solution of 453-1 (100 mg, 0.493 mmol) in SOCl₂ (3 mL) was addedDMF (one drop) at 0° C., and stirred at r.t. for 1 h. The mixture wasco-evaporated with toluene (2×), and re-dissolved in anhydrous DCM (5mL). The solution was treated with TEA (99.6 mg, 0.986 mol) and 453-3(164.2 mg, 0.493 mol). The mixture was stirred at r.t. for 1 h. Themixture was diluted with DCM (20 mL) and washed with brine (20 mL). Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by prep-HPLC to give 453 (42mg, yield: 16.7%). +ESI-MS: m/z 512.1 [M+H]⁺.

Example 237 Preparation of Compound 454

Compound 454-2 was prepared essentially as described in the preparationof 406 by using 454-1 and prop-1-en-2-yl magnesium bromide. Crude 454-2was purified by column chromatography (PE:EA 8:1) to give 454-2 as asolid (0.8 g). +ESI-MS: m/z 401.9 [M+H]⁺.

To a solution of 454-2 (800 mg, 2.0 mmol) in DMSO (10 mL) was added NaN₃(650 mg, 10.0 mmol) at r.t., and the mixture was stirred for 5 h. Thereaction was quenched with water (30 mL), and extracted by EA (3×20 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 6:1) to give 454-3 (402 mg, 55.1%) as awhite solid. +ESI-MS: m/z 362.9 [M+H]⁺.

Ozone was bubbled into a solution of 454-3 (402 mg, 1.1 mmol) inanhydrous methanol (20 mL) at −78° C. for 10 mins. After excess ozonewas purged by nitrogen, NaBH₄ (125 mg, 3.3 mmol) was added. The mixturewas stirred at r.t. for 30 mins. The reaction was quenched with waterand extracted with EA (3×30 mL). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (PE:EA 5:1)to give 454-4 as an oil (303 mg, 74.6%).

Compound 454 was prepared essentially as described in the preparation of428 from 454-4 and 454-7. Crude 454 was purified by prep-HPLC to give454 as a white solid (40 mg, 31.4%). +ESI-MS: m/z 531.0 [M+H]⁺.

Example 238 Preparation of Compounds 455, 456, 457 and 458

Compound 455-2 was prepared essentially as described in PCT PublicationNo. WO 2012/057247, published May 3, 2012, which is hereby incorporatedby reference for the limited purpose of its description of thepreparation of 455-2. To a solution of 455-2 (2.0 g, 9.17 mmol) in DCM(50 mL) was added DAST (6.0 g, 36 mmol) at 0° C., and the mixture wasstirred at r.t. for 1 h. The reaction was quenched with water (50 mL).The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 100:1) to give 455-3 (1.2 g, 60%).

To a solution of 455-3 (1.2 g, 5.4 mmol) in anhydrous THF (40 mL) wasadded n-BuLi (3 mL, 2.5M in hexane) dropwise at −78° C., and thesolution was stirred for 1 h.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 8.1 mmol)was added dropwise, and the mixture was stirred at −78° C. for 1 h. Thereaction was quenched with water (50 mL), and extracted with EA (2×50mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (PE:EA 100:1) to give 455-4 (0.4g, 28%).

Compounds 455-5 to 455-7 was prepared essentially as described in thepreparation of 449 by using 455-4. Crude 455-7 was purified by gelcolumn to give 455-7 (0.9 g, 67%). A suspension of 455-7 (1.0 g, 2.9mmol) and SnCl₂.H₂O (2.6 g, 12 mmol) in EA (15 mL) was stirred at 70° C.overnight. After cooling to r.t., NH₃.H₂O (5 mL) was added, and themixture was stirred for 30 mins. A white precipitate was formed andremoved by filtration. The filtrate was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Compound 455-8(0.8 g) was used without further purification.

Compound 455-9 was prepared essentially as described in the preparationof 406 by using 455-8 and 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid.Crude 455-9 was purified by prep-HPLC to give 455-9 as a white solid(570 mg, 41%). +ESI-MS: m/z 521.8 [M+H]⁺. Compound 455-9 (570 mg, 1.09mmol) separated via SFC separation to give two enantiomers: 455-10 (230mg) and 455-11 (220 mg, 42%).

To a solution of 455-10 (100 mg, 0.19 mmol) and 455-4 (150 mg, 0.56mmol) in co-solvent dioxane (4 mL) and H₂O (0.5 mL) were addedPd(dppf)Cl₂ (10 mg, 0.012 mmol) and K₂CO₃ (55 mg, 0.4 mmol). The mixturewas degassed and then refilled with N₂ (3×). The mixture was heated to150° C. by microwave for 50 mins. The mixture was cooled to r.t., anddiluted with EA (30 mL) and water (30 mL). The organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-HPLC to give 455-12 as awhite solid (80 mg, 70%).

Compound 455-12 (80 mg, 0.15 mmol) was separated via SFC separation togive two isomers: 457 (30 mg) and 458 (29 mg). 457: +ESI-MS: m/z 584.1[M+H]⁺. 458: +ESI-MS: m/z 584.1 [M+H]⁺.

Compound 456 was prepared by using 455-11 and 455-4. Crude 456 waspurified by prep-HPLC to give 456 as a white solid (75 mg, 65%).+ESI-MS: m/z 584.1 [M+H]⁺. Compound 455 was prepared by using 455-9 and455-4. Crude 455 was purified by prep-HPLC to give 455 as a white solid(40 mg, 23.3%). +ESI-MS: m/z 584.1 [M+H]⁺.

Example 239 Preparation of Compound 459

Compound 459-2 was prepared essentially as described in Hay et al., J.Med Chem. (2010) 53(2):787-797, which is hereby incorporated byreference for the limited purpose of its description of the preparationof 459-2. Compound 459-3 was prepared essentially as described in PCTPublication No. WO 2012/020786, published Feb. 16, 2012, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 459-3.

To a solution of NaBH₄ (60 mg, 1.58 mmol) in a mixture of THF (5 mL) andMeOH (1 mL) was added 459-3 (150 mg, 0.794 mol) in portions. The mixturewas stirred at r.t. for 1 h. The reaction was quenched with water (10mL), and extracted with EA (3×10 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(10-20% EA in PE) to give 459-4 (97 mg, 63.8%).

To a solution of 459-4 (573 mg, 3.0 mmol), isoindoline-1,3-dione (441mg, 3.0 mmol) and PPh₃ (943 mg, 3.0 mmol) in anhydrous THF (15 mL) wasadded DIAD (727 mg, 3.0 mmol) dropwise at 0° C. under N₂. The mixturewas stirred for 2 h at r.t. The reaction was quenched by sat. NaHCO₃solution (30 mL). The mixture was extracted with DCM (3×20 mL). Thecombined organic layers were washed with brine, dried over anhydrousMgSO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 10:1) to give 459-5 (604 mg, 62.9%).

Compounds 459-5 to 459-12 was prepared essentially as described in thepreparation of 428. Crude 459-12 was purified by flash columnchromatography (10-20% EA in PE) to give 459-12 (127 mg, 65.8%). Asuspension of 459-12 (127 mg, 0.326 mmol) in N₂H₄H₂O (10 mL) was stirredat r.t. for 2 h. The mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC to give 459 (35 mg, 33.9%).+ESI-MS: m/z 568.0 [M+H]⁺.

Example 240 Preparation of Compound 460

Compounds 460-1 to 460-6 were prepared essentially as described in thepreparation of 272 and 403. Crude 460-6 was purified by prep-HPLC togive 460-6 as a white solid (67 mg, 50%). To a solution of 460-6 (100mg, 0.16 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture wasstirred at r.t. for 1 h. and then concentrated under reduced pressure.The residue was purified by prep-HPLC to give 460 (30 mg, 60%). +ESI-MS:m/z 528.1 [M+H]⁺.

Example 241 Preparation of Compound 461

Compound 461-2 was prepared essentially as described in PCT PublicationNo. WO 2013/055645, published Apr. 18, 2013, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 461-2. Compound 461-3 was prepared essentially asdescribed in Podlech et al., Helv. Chimica Acta (1995) 78(5): 1238-1246,which is hereby incorporated by reference for the limited purpose of itsdescription of the preparation of 461-3. Compound 461-4 was preparedessentially as described in PCT Publication No. WO 2009/154780,published Dec. 23, 2009, which is hereby incorporated by reference forthe limited purpose of its description of the preparation of 461-4.

To a solution of 461-4 (9.0 g, 39.3 mmol) in anhydrous DMF (50 mL) wereadded DIPEA (15.2 g, 117.9 mmol) and HATU (14.9 g, 39.3 mmol), and themixture was stirred at r.t. for 30 mins. N,O-dimethylhydroxylamine (3.85g, 39.3 mmol) was added, and the mixture was stirred at r.t. for 2 h.The mixture was diluted with water (100 mL), and extracted with EA(3×100 mL). The combined organic phase was washed brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (PE:EA 10:1) to give 461-5 (8.5 g,70.7%).

To a solution of 461-5 (8.0 g, 31.0 mmol) and2-bromo-6-iodo-3-methoxypyridine (9.7 g, 31.0 mmol) in anhydrous THF(120 mL) was added i-PrMgCl (23.5 mL, 46.51 mmol) dropwise at 0° C., andthe mixture was stirred at r.t. for 2 h. The reaction was quenched withwater (50 mL) and extracted with EA (3×150 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 8:1) to give 461-6 (6.0 g, 49.6%). +ESI-MS: m/z385.01 [M+H]⁺.

Compound 461-7 was prepared as essentially as described in thepreparation of 428 by using 461-6. Compound 461-7 (4.2 g) was obtainedafter purification by column chromatography.

To a suspension of CH₃P⁺Ph₃Br⁻ (2.46 g, 6.92 mmol) in toluene (20 mL)was added NaHMDS (6.92 mL, 1 M in THF) dropwise at 0° C. under N₂. Themixture was stirred for 30 mins. The mixture was cooled to −78° C. and461-7 (2.0 g, 4.6 mmol) was added, and then stirred at −78° C. to refluxovernight. The reaction was quenched by water (30 mL) and extracted withEA (3×30 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (PE:EA 5:1) to give 461-8(1.2 g, 61.0%).

To a solution of 461-8 (1.3 g, 3.0 mmol) in DCM (20 mL) were added NMO(1.05 g, 9.0 mmol) and OsO₄ (38.4 mg, 0.15 mmol), and the mixture wasstirred at r.t. overnight. The reaction was quenched with sat. Na₂SO₃solution (50 mL) and extracted with EA (3×50 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 3:1) to give 461-9 (0.85 g, 60.7%).

To an ice-cold solution of 461-9 (265 mg, 0.725 mmol) and TEA (220 mg,2.2 mmol) in anhydrous DCM (20 mL) was added MsCl (1.0 g, 8.7 mmol)dropwise, and the mixture was stirred at r.t. for 1 h. The mixture waswashed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography (PE:EA 5:1) to give 461-10 (250 mg, 63.4%).

Compound 461 was prepared essentially as described in the preparation of428 from 461-10. Crude 461 was purified by prep-HPLC to give 461 as awhite solid (36 mg, 20.2%). +ESI-MS: m/z 556.1 [M+H]⁺.

Example 242 Preparation of Compound 462

To a solution of 462-1 (3.56 g, 10.0 mmol) in DMSO (30 mL) was addedNaN₃ (1.95 g, 30.0 mmol) at 25° C. in portions, and the mixture wasstirred for 30 mins. The mixture was poured into water (50 mL), andextracted with EA (3×30 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (PE:EA 5:1)to give 462-2 (2.4 g, 75.1%) as a white solid. +ESI-MS: m/z 320.9[M+H]⁺.

To a solution of 462-2 (2.4 g, 7.5 mmol) in anhydrous THF (30 mL) wasadded vinyl-magnesium bromide (7.5 mL, 1.0M in THF) dropwise at −30° C.under N₂, and the mixture was stirred for 30 mins. The reaction wasquenched with sat. NH₄Cl solution (50 mL). The mixture was allowed towarm to r.t. and extracted with EA (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 5:1) to give 462-3 as a white solid (2.0 g,76.9%). +ESI-MS: m/z 349.0 [M+H]⁺.

Ozone was bubbled into a solution of 462-3 (2.0 g, 5.7 mmol) inanhydrous MeOH (20 mL) at −78° C. for 10 mins. After excess Ozone waspurged by N₂, NaBH₄ (800 mg, 21.1 mmol) was added at r.t. in portions.The mixture was stirred at r.t. for 30 mins. The reaction was quenchedwith water (30 mL) and extracted with EA (2×50 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 1:1) to give 462-4 as an oil (1.6 g, 80.1%).+ESI-MS: m/z 352.9 [M+H]⁺.

To a solution of 462-4 (1.6 g, 4.5 mmol) and TEA (900 mg, 8.9 mmol) inanhydrous DCM (20 mL) was added MsCl (500 mg, 4.4 mmol) dropwise at 0°C. The solution was stirred at r.t. for 30 mins. The reaction wasquenched with H₂O (30 mL) and extracted with EA (3×30 mL). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 4:1) to give 462-5 as a solid (1.6 g, 84.2%).+ESI-MS: m/z 431 [M+H]⁺.

To a solution of 462-5 (1.6 g, 3.7 mmol) in CH₃CN (20 mL) was addedazetidine hydrochloride (1.6 g, 17.2 mmol) at r.t. The solution washeated to 70° C. and stirred for 8 h. After cooling to r.t., thereaction was quenched with H₂O (30 mL) and extracted with EA (3×30 mL).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 1:1) to give 462-6 as an oil (500 mg,35.7%). +ESI-MS: m/z 391.9 [M+H]⁺.

Compound 462 was prepared essentially as described in the preparation of428 by using 462-6. Crude 462 was purified by prep-HPLC to give 462 as awhite solid (10 mg, 6.5%). +ESI-MS: m/z 556.1 [M+H]⁺.

Example 243 Preparation of Compound 463

Compound 463 was prepared essentially as described in the preparation of461 by using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid.Compound 463 was obtained as white solid (40 mg, 40%). +ESI-MS: m/z542.1 [M+H]⁺.

Example 244 Preparation of Compound 464

Compound 464-2 was prepared essentially as described in Zomik et al.,Chem. Eur. J. (2011) 17(5):1473-1484 and S1473/1-S1473/121, which ishereby incorporated by reference for the limited purpose of itsdescription of the preparation of 464-2. Compound 464-10 was preparedessentially as described in the preparation of 272 by using 464-2.Compound 464-10 was obtained as white solid (300 mg, 68.5%). +ESI-MS:m/z 582.9 [M+H]⁺.

To a solution of 464-10 (50 mg, 0.086 mmol) in 1,4-dioxane (5 mL) wasadded ammonia water (2 mL) in a sealed tube. The mixture was thenstirred at 100° C. overnight. After cooling to r.t., the mixture wasconcentrated to dryness, and the residue was purified by prep-HPLC togive 464 (15 mg, 30.8%) as a white solid. +ESI-MS: m/z 568.0 [M+H]⁺.

Example 245 Preparation of Compound 465

To a stirred solution of 465-1 (87.3 mg, 0.15 mmol) in THF (5 mL) at 0°C. was added LAH (5.7 mg, 0.15 mmol) under N₂. After stirring at 0° C.for 1 h, the reaction was quenched by water (10 mL), and extracted by EA(3×10 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated to dryness. The residue was purifiedby prep-HPLC to give 465 (50 mg, 60.2%) as a white solid. +ESI-MS: m/z555.0 [M+H]⁺.

Example 246 Preparation of Compound 466

Compound 466 was prepared essentially as described in the preparation of459 by using 1-(2,6-dichloropyridin-4-yl)ethanone. Compound 466 wasobtained as white solid (20 mg, 18.5%). +ESI-MS: m/z 582.1 [M+H]⁺.

Example 247 Preparation of Compound 467

To a solution of 467-1 (60 mg, 0.12 mmol) in THF (4 mL) was added MeMgCl(1 mL, 3 M in ether) dropwise at 0° C., and the mixture was stirred atfor 1 h. The reaction was quenched with sat. NH₄Cl solution, andextracted with EA (3×10 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-HPLC to give 467 (30 mg, 47%)as a white solid. +ESI-MS: m/z 531.3 [M+H]⁺.

Example 248 Preparation of Compound 468

To a solution of 468-1 (2.4 g, 20 mmol) in anhydrous THF (50 mL) wasadded n-BuLi (8 mL, 2.5M in hexane) at −78° C. under N₂, and the mixturewas stirred for 0.5 h. The mixture was treated withtributylchlorostannane (6.5 g, 20 mmol) in portions, and stirred at −78°C. for 1 h. The reaction was quenched by water (50 mL), and extractedwith EA (3×50 mL). The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (PE:EA 10:1) to give 468-2(6 g, 74%).

A mixture of 468-2 (2.02 g, 5.0 mmol), Pd(dppf)Cl₂ (90 mg, 2% eq.) and1-(6-bromo-5-methoxypyridin-2-yl)-2,2,2-trifluoroethanone (1.5 g, 5 mL)was dissolved in dry DMF (10 mL) under N2. The mixture was heated to130° C. by microwave and stirred for 0.5 h. After cooling to r.t., themixture was poured into water (50 mL) and extracted with EA (3×30 mL).The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 5:1) to give 468-3 (1.4 g, 82%).

Compound 468 was prepared essentially as described in the preparation of424 by using 468-3. Crude 468 was purified by pre-HPLC to give 468 as awhite solid (50 mg, 20%). +ESI-MS: m/z 547.9 [M+H]⁺.

Example 249 Preparation of Compound 469

Compound 469 was prepared according to the method described in thepreparation of 176. LCMS: m/z 553.10 [M+H]⁺.

Example 250 Preparation of Compound 135

Compound 135-2 was prepared essentially as described in Granzhan et al.,Angew. Chem. Int'l Ed (2010) 49(32): 5515-5518, S5515/1-S5515/30, whichis hereby incorporated by reference for the limited purpose of itsdescription of the preparation of 135-2.

To a solution of 135-2 (10.0 g, 57.8 mmol) in anhydrous THF (60 mL) wasadded n-BuLi (35 mL, 2.5 M in hexane) dropwise at −78° C. under N₂. Themixture was stirred at −78° C. for 30 mins, under N2 and oxirane (15.5mL, 289 mmol) was added. The mixture was warmed to r.t. and stirred for2 h. The reaction was quenched with H₂O, and extracted with EA (3×100mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (PE:EA 3:1) to give 135-3 (3.5 g,28%). +ESI-MS: m/z 217.9 [M+H]⁺.

To a solution of 135-3 (3.5 g, 16.1 mmol) in MeOH (60 mL) was addedcone. HCl solution (15 mL, 12 N) at r.t., and stirred at 60° C. for 5 h.The reaction was quenched with sat. NaHCO₃ solution, and extracted withEA (3×50 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (PE:EA 1:1) to give 135-4(1.02 g, 36%).

To a solution of 135-4 (1.02 g, 5.7 mmol) and K₂CO₃ (1.5 g, 11.5 mmol)in a mixture of THF (10 mL) and H₂O (10 mL) was added I₂ (1.5 g, 6.0mmol) in portions, and the mixture was stirred at r.t. for 30 mins. Thereaction was quenched with sat. NaS₂O₃ solution, and extracted with EA(3×50 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (PE:EA 2:1) to give 135-5 (1.1 g,62.5%).

To a solution of 135-5 (1.1 g, 3.7 mmol) and PPh₃ (1.5 g, 5.7 mmol) inanhydrous THF (10 mL) was added DIAD (1.2 g, 5.7 mmol) at r.t. under N2.The mixture was heated to 70° C. for 1 h and then cooled to r.t. Thereaction was quenched with H₂O, and extracted with EA (3×30 mL). Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EA 2:1) to give 135-6 (0.8 g, 78%).+ESI-MS: m/z 281.8 [M+H]⁺.

To a solution of 135-6 (0.8 g, 7.1 mmol) and 135-7 (2.2 g, 7.1 mmol) inTHF (10 mL) was added i-PrMgBr (21 mL, 1.0 M in THF) dropwise under N2,and the mixture was stirred at r.t. for 1 h. The reaction was quenchedwith sat. NH₄Cl solution and extracted with EA (3×30 mL). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 1:1) to give 135-8 (1.2 g, 77%). +ESI-MS: m/z408.9 [M+H]⁺.

To a solution of 135-8 (408 mg, 1.0 mmol),(3-chloro-4-fluorophenyl)boronic acid (175 mg, 1.0 mmol) and Cs₂CO₃ (276mg, 2.0 mmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl₂(82 mg, 0.1 mmol) under N2. The mixture was heated to 120° C. undermicrowave irradiation and stirred for 30 mins. The mixture was cooled tor.t., poured into cold H₂O and extracted with EA (3×10 mL). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 135 (80 mg) as a white solid. +ESI-MS: m/z 502.9[M+H]⁺.

Example 251 Preparation of Compound 470

To a solution of 470-1 (1.7 g, 6.7 mmol) in DCM (10 mL) was added DAST(3 mL) at 0° C., and the mixture was stirred at 0° C. for 30 mins. Theresulting was quenched with sat. NaHCO₃ solution at 0° C. and extractedby EA (3×20 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (PE:EA 15:1) to give 470-2as a white solid (800 mg, 47.1%).

To a solution of 470-2 (254 mg, 1.0 mmol) in MeOH (5 mL) was added NaOH(5 mL, 2N), and the mixture was stirred at reflux for 1 h. The mixturewas cooled to r.t. and acidified to pH 4˜5 using HCl (2 M). The mixturewas extracted with EA (3×20 mL). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give 470-3 as a white solid (100 mg, 41.6%).

To a solution of 470-3 (100 mg, 0.42 mmol), HATU (190 mg, 0.5 mmol) andDIPEA (129 mg, 1.0 mmol) in anhydrous DCM (5 mL) was added 470-4 (140mg, 0.39 mmol) at 25° C. The solution was stirred for 1 h and thenquenched with aq. NaHCO₃ solution. The aqueous phase was extracted withDCM (2×10 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-HPLC to give 470 as a white solid (60 mg,24.5%). +ESI-MS: m/z 586.9 [M+H]⁺.

Example 252 Preparation of Compound 471

To a solution of bromide 471-1 (5.0 g, 28.9 mmol) and(3-chloro-4-fluorophenyl)boronic acid (5.5 g, 31.8 mmol) in dioxane (50mL) were added Pd(dppf)Cl₂ (816 mg, 1.0 mmol) and a freshly preparedCs₂CO₃ solution (11 g in 50 mL of water) under N2. The mixture wasstirred at 70° C. for 3 h. The solution was cooled to r.t., poured intoice water and extracted with EA (3×100 mL). The combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography (PE:EA 10:1˜5:1) to give 471-2 (5.5 g) as a white solid.

To a solution of 471-2 (3.9 g, 17.4 mmol) and K₂CO₃ (3.0 g, 21.7 mmol)in DMF (50 mL) was added I₂ (1.4 g, 5.5 mmol) in portions at r.t., andthe mixture was stirred for 2 h. The reaction was quenched with sat.Na₂S₂O₃ solution, and extracted with EA (3×50 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (PE:EA 50:1˜25:1) to give 471-3 as a white solid (2.1 g,50%). +ESI-MS: m/z 349.8 [M+H]⁺.

To a solution of 471-3 (2.0 g, 5.7 mmol) and K₂CO₃ (790 mg, 5.7 mmol) inDMF (25 mL) was added MeI (1.5 g, 11 mmol) dropwise at 0° C. The mixturewas stirred at r.t. for 2 h. The reaction was quenched with water, andextracted with EA (3×50 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (PE:EA 50:1)to give 471-4 as a white solid (1.1 g, 55%).

To a solution of 471-4 (1.1 g, 3.0 mmol), picolinic acid hydrochloride(240 mg, 1.5 mmol), Cs₂CO₃ (2.8 g, 8.7 mmol) and CuI (165 mg, 0.75 mmol)in DMF (20 mL) was added ethyl 2-cyanoacetate (650 mg, 6.0 mmol) underN2. The mixture was heated to 130° C. under microwave irradiation andstirred for 30 mins. The mixture was cooled to r.t., poured into waterand extracted with EA (3×30 mL). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (PE:EA10:1˜5:1) to give 471-5 as a yellow solid (720 mg, 65%). +ESI-MS: m/z348.8 [M+H]⁺.

To a solution of 471-5 (720 mg, 2.04 mmol) in anhydrous DMF (15 mL) wasadded NaH (130 mg, 3.12 mmol) in portions at 0° C. After stirring for 30mins., Mel (840 mg, 6 mmol) was added. The mixture was stirred at 0° C.for 2 h. The reaction was quenched with water, and extracted with EA(3×30 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (PE:EA 25:1) to give 471-6 as awhite solid (468 mg, 65%). +ESI-MS: m/z 362.8 [M+H]⁺.

To a solution of 471-6 (460 mg, 1.27 mmol) in anhydrous THF (15 mL) wasadded LAH (250 mg, 5 mmol) at 0° C. under N2, and the mixture stirred at0° C. for 2 h. The reaction was quenched with water, and extracted withEA (3×30 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC to give 471-7 (150 mg, 36%). +ESI-MS:m/z 324.8 [M+H]⁺.

To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (60 mg, 0.3mmol), HATU (70 mg, 0.5 mmol) and DIEA (300 mg, 0.7 mmol) in DCM (15 mL)was added amine 471-7 (100 mg, 0.3 mmol). After stirring at r.t. for 30mins., the reaction was quenched with sat. NaHCO₃ solution, andextracted with DCM (3×10 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-HPLC to give 471 as a whitesolid (55 mg, 32%). +ESI-MS: m/z 519.0 [M+H]⁺.

Example 253 Preparation of Compounds 509-513

Potassium carbonate (29.8 g, 216 mmol) and trifluoroacetaldehyde ethylhemiacetal (19 mL, 162 mmol) were sequentially added to a suspension of509-1 (14.0 g, 108 mmol) in water (210 mL). The reaction was stirred at100° C. overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (19mL, 162 mmol) was added. The reaction was stirred at 100° C. for 7 h,and further trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) wasadded. After 16 h at 100° C., the reaction was cooled to 0° C.,neutralized with 1M aq. HCl solution and extracted with EtOAc. Theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,100:0 to 70:30) afforded 509-2 (24.0 g, 80% purity A/A UV).

Iodine (40.1 g, 158 mmol) was added to a solution of 509-2 (24.0 g) andpotassium carbonate (28.9 g, 210 mmol) in water (350 mL). The mixturewas stirred at r.t. overnight. A 1M aq. sodium thiosulfate solution wasadded. The mixture was treated with 3N aq. HCl until a white solidformed. EtOAc was added and the layers were separated. The aqueous phasewas extracted with EtOAc (3×). The combined organic portions were driedwith Na₂SO₄ and filtered. The solvents were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to70:30) afforded 509-3 as a white solid (21.0 g, 50% over two steps).UPLC/MS(ES⁺) m/z: 354.03 [M+H]⁺.

Chloroacetone (2.6 mL, 32.8 mmol) was added to a solution of 509-3 (10.5g, 29.8 mmol) and potassium carbonate (6.18 g, 44.8 mmol) in acetone(170 mL). The reaction was stirred at 50° C. overnight. The volatileswere removed under reduced pressure, and the residue was partitionedbetween water and EtOAc. The layers were separated, and the organicportion was dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was tritrated with DCM, and the precipitate driedto afford 509-4 as a white solid (6.80 g, 55%). UPLC/MS(ES⁺) m/z: 409.92[M+H]⁺. The supernatant was concentrated under reduced pressure, and theresidue chromatographed (cyclohexane:EtOAc, 100:0 to 0:100) to affordunreacted 509-3 (1.20 g, 11%).

The reaction was performed in 8 batches. A mixture of 509-4 (841 mg,2.05 mmol), 2-methylpropane-2-sulfinamide (273 mg, 2.26 mmol) andtitanium(IV) ethoxide (1.03 g, 4.51 mmol) in THF (16 mL) was heated to70° C. (sealed vial, degassed and purged with N₂). The mixture wasstirred at 70° C. for 3 h. The 8 batches were unified. EtOAc and waterwere added. The mixture was stirred for 5 mins, and then filteredthrough a pad of celite. The layers were separated, and the aqueousportion was extracted with EtOAc. The combined organic portions weredried with Na₂SO₄ and filtered. The volatiles were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50 to0:100) afforded 509-5 (5.36 g, 63%). UPLC/MS(ES⁺): m/z 513.10 [M+H]⁺.

n-Buthyllithium (1.6M solution in THF, 6.60 mL, 10.5 mmol) was added toa solution of EtMgBr (1M in THF, 5.23 mL, 5.23 mmol) in THF (15 mL),which had been pre-cooled to 0° C. After 10 mins, the mixture was cooledto −78° C. A solution of 509-5 (2.68 g, 5.23 mmol) in THF (15 mL) wasadded dropwise. The reaction was stirred at −78° C. for 15 mins. Thereaction was quenched with MeOH and diluted with EtOAc. The organicportion was washed with brine, and the aqueous portion extracted withEtOAc. The combined organic portions were dried with Na₂SO₄, filteredand concentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 509-6 as a yellow wax (2.60g, 64%).

Dess-Martin periodinane (3.14 g, 7.46 mmol) was added to a stirredsolution of 509-6 (2.60 g, 6.73 mmol) in DCM (36 mL). The reaction wasstirred at r.t. under N₂ atmosphere for 3 h. The reaction was quenchedwith a 1:1 mixture of 2M aq. Na₂S₂O₃ and sat. aq. NaHCO₃. After 30 minsof vigorous stirring, the layers were separated. The organic portion waswashed with brine, dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,100:0 to 50:50) afforded 509-7 as a white solid (2.11 g, 81%).UPLC/MS(ES⁺): m/z 385.16 [M+H]⁺, 403.18 [M+H30]⁺.

The reaction was performed in 2 batches. Trimethylsulfoxonium iodide(601 mg, 2.73 mmol) was added in 1 portion to a mixture of tBuOK (305mg, 2.73 mmol) in CH₃CN (50 mL), which had been previously degassed. Themixture was further degassed and stirred at r.t. for 30 mins. Thesolution containing the ylide was filtered from the solid and added to asolution of 509-7 (1.05 g, 2.73 mmol) in CH₃CN (50 mL), which had beenpreviously degassed. The reaction was stirred at r.t. for 1 h. The 2batches were combined, and the volatiles were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to50:50) afforded 509-8 as a colorless wax (1.45 g, 66%). UPLC/MS(ES⁺):m/z 399.14 [M+H]⁺.

A solution of 509-8 (1.45 g, 3.64 mmol) in 7M NH₃-MeOH (800 mL) wasstirred at r.t. for 2 h. The volatiles were removed under reducedpressure to afford 509-9 (1.43 g), which was used in the next step.

Method A: A mixture of 509-9 (750 mg), EDC (448 mg, 2.35 mmol), HOBT(317 mg, 2.35 mmol), TEA (500 uL, 3.60 mmol) and acid (1.80 mmol) in DCM(18 mL) was stirred at r.t. for 2 h. Water was added, and the mixturewas stirred for 10 mins. The layers were separated, and the organicportion was dried with Na₂SO₄. The solvent was evaporated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc) afforded509-10.

Method B: A solution of acid (0.120 mmol), HATU (44 mg) and DIPEA (110uL) in DMF or DCM (1 mL) was stirred at r.t. for 15 mins. A solution of509-9 (50 mg) in DMF (or DCM, 1 mL) was added to the reaction. Themixture was stirred at r.t. for 20 mins. The majority of the volatileswere removed under reduced pressure. The residue was taken up withEtOAc, and the organic portion was washed with 1M aq. NaOH and 1M aq.HCl, dried with Na₂SO₄, filtered and concentrated under reduced pressureto give 509-10.

A mixture of 509-10 (0.582 mmol), boronic acid (0.872 mmol), K₃PO₄ (247mg, 1.16 mmol), KH₂PO₄ (158 mg, 1.16 mmol) and Pd(dbpf)Cl₂ (13.8 mg,0.029 mmol) in a DME:EtOH:H₂O mixture (5:3:1, 9 mL) was degassed andwarmed to 50° C. for 6 h. DCM and water were added. The layers wereseparated, and the organic portion was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc) afforded 509-11.

A 4M HCl-dioxane solution (1 mL) was added to a solution of 509-11(0.508 mmol) in MeOH (5 mL). After 15 mins, the volatiles were removedunder reduced pressure. The residue was dissolved in DCM. The organicportion was washed with 5% aq. NaHCO₃ solution and water, dried withNa₂SO₄, filtered and concentrated under reduced pressure to afford509-12.

Coupling of 509-9 with 4-cyclopropoxy-3-methoxybenzoic acid according toMethod A afforded 509-10A as a white solid (85%). UPLC/MS(ES⁺): m/z606.24 [M+H]⁺. Suzuki coupling of 509-10A with 4-fluorophenylboronicacid followed by sulfinamide hydrolysis afforded 509 as a white solid(53% over two steps). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

509 (53 mg) was dissolved in DCM. The solution was washed with sat. aq.NaHCO₃ solution, dried with Na₂SO₄, filtered and concentrated underreduced pressure. The amine was resolved by prep-HPLC [Chiralpak AD-H(25×3 cm, 5 um), mobile phase: n-hexane/(ethanol+0.1% ipa) 80:20% v/v,flow rate: 32 mL/min, UV detection DAD 220 nm]. Two fractions wererecovered based on retention times: a mixture of 510, 512 and 513:t_(R)=21.0 min; and 511: white solid (7.3 mg, t_(R)=28.5 min).UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

The mixture of 510, 512 and 513 was resolved by prep-HPLC [Chiralpak IC(25×3 cm, 5 um), mobile phase: n-hexane/(ethanol+0.1% ipa) 70/30% v/v,flow rate: 32 mL/min, ETV detection DAD 220 nm]. Two fractions wererecovered based on retention times: a mixture of 512 and 513: t_(R)=8.2min; and 510: white solid (7.1 mg, t_(R)=10.6 min). UPLC/MS(ES⁺): m/z562.20 [M+H]⁺.

The mixture of 512 and 513 was resolved by prep-HPLC [Chiralpak OJ-H(25×3 cm, 5 um), mobile phase: n-hexane/(ethanol/MeOH 1/1+0.1% ipa)65/35% v/v, flow rate: 38 mL/min, UV detection DAD 220 nm]. Twofractions were recovered based on retention times: 512: white solid (6.0mg, t_(R)=7.2 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺; and 513: whitesolid (6.0 mg, t_(R)=11.3 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

Alternatively, 509 (220 mg) was resolved by prep-HPLC [Chiralpak IC(25×2 cm, 5 um), mobile phase: n-hexane/(ethanol/methanol 1/1+0.1% ipa)86/14% v/v, flow rate: 16 mL/min, UV detection DAD 220 nm]. Threefractions were recovered based on retention times: a mixture of 512 and513: (104 mg, t_(R)=13.4 min); 511: (40 mg, 14%, t_(R)=15.0 min).UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺; and 510: (35 mg, 12%, t_(R)=17.5 min).UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

The mixture of 512 and 513: was resolved by prep-HPLC [Chiralcel OJ-H(25×3 cm, 5 um), mobile phase: n-hexane/(ethanol/methanol 1/1+0.1% ipa)65/35% v/v, flow rate: 40 mL/min, UV detection DAD 220 nm]. Twofractions were recovered based on retention times: 512 (41 mg, 14%,t_(R)=7.5 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺; and 513 (46.6 mg, 16%,t_(R)=12.0 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

Example 254 Preparation of Compound 542

Suzuki coupling of 509-10A with 4-cyanophenylboronic acid followed byhydrolysis of the resulting sulfinamide afforded 542 (78% over 2 steps).UPLC/MS(ES⁺): m/z 569.40 [M+H]⁺.

Example 255 Preparation of Compound 539

Coupling of 509-9 (50 mg) with4-(2-(4-methoxybenzyloxy)ethoxy)-3-methoxybenzoic acid according toMethod B afforded 509-10B. Suzuki coupling of 509-10B with4-fluorophenylboronic acid followed by sulfinamide hydrolysis andPMB-group removal afforded 539 as an off-white solid (10 mg).UPLC/MS(ES⁺): m/z 566.30 [M+H]⁺.

Example 256 Preparation of Compound 543

Coupling of 509-9 (80 mg) with 4-(carbamoylmethoxy)-3-methoxybenzoicacid according to Method B afforded 509-10 C. Suzuki coupling of 509-10Cwith 4-fluorophenylboronic acid followed by sulfamide hydrolysisafforded 543 as an off-white solid (8.7 mg). UPLC/MS(ES⁺): m/z 579.40[M+H]⁺.

Example 257 Preparation of Compound 556

Coupling of 509-9 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acidaccording to Method A afforded 509-10D. UPLC/MS(ES⁺): m/z 624.20 [M+H]⁺.Suzuki coupling of 509-10D with 4-fluorophenylboronic acid followed bysulfamide hydrolysis afforded 556 as an off-white solid (50% over 2steps). UPLC/MS(ES⁺): m/z 580.33 [M+H]⁺.

Example 258 Preparation of Compounds 494, 498, 482 and 483

A mixture of 509-2 (5.00 g, 22.0 mmol), (3-chloro-4-fluorophenyl)boronicacid (7.66 g, 44.0 mmol), Pd(dppf)Cl₂ (1.60 g, 2.20 mmol) and Na₂CO₃ (2Maq solution, 22.0 mL, 44.0 mmol) in DCE (250 mL) was degassed and heatedto reflux for 16 h. Additional Pd(dppf)Cl₂ (0.05 eq),(3-chloro-4-fluorophenyl)boronic acid (1 eq.) and aq Na₂CO₃ (1 eq) wereadded. The reaction was refluxed for 4 h and then water was added. Thelayers were separated, and the aqueous portion was extracted with EtOAc.The combined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:DCM, 70:30 to 0:100) afforded 494-13 as a yellow solid(2.74 g). UPLC/MS(ES⁺): m/z 322.10 [M+H]⁺.

Iodine (1.77 g, 6.98 mmol) was added to a solution of 494-13 (2.24 g,6.98 mmol) and potassium carbonate (2.89 g, 20.9 mmol) in water (100mL). The mixture was stirred at r.t. for 30 mins. A 1M aq. sodiumthiosulfate solution was added. The mixture was treated with 3N aq. HCluntil a white solid formed. EtOAc was added, and the layers wereseparated. The aqueous phase was extracted with EtOAc. The combinedorganic portions were dried with Na₂SO₄ and filtered. The solvents wereremoved under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 80:20) afforded 494-14 as a light yellowsolid (2.80 g, 90%). UPLC/MS(ES⁺): m/z 448.05 [M+H]⁺.

Chloroacetone (548 μL, 6.89 mmol) was added to a solution of 494-14(2.80 g, 6.26 mmol) and potassium carbonate (1.30 g, 9.40 mmol) inacetone (40 mL). The reaction was stirred at 50° C. for 24 h. Thevolatiles were removed under reduced pressure, and the residue waspartitioned between water and EtOAc. The layers were separated, and theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:DCM, 60:40to 30:70) afforded 494-15 as a white solid (2.38 g, 75%). UPLC/MS(ES⁺):m/z 504.27 [M+H]⁺.

A mixture of 494-15 (1.87 g, 3.72 mmol), 2-methylpropane-2-sulfamide(495 mg, 4.09 mmol) and titanium(IV) ethoxide (1.86 g, 8.18 mmol) in THF(30 mL) was heated to 70° C. (sealed vial, degassed and purged with N₂).The mixture was stirred at 70° C. overnight. EtOAc and water were added.The mixture was filtered through a pad of celite. The layers wereseparated, and the organic portion was dried with Na₂SO₄ and filtered.The volatiles were removed under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 80:20 to 20:80) afforded 494-16 as a lightyellow solid (1.00 g, 45%). UPLC/MS(ES⁺): m/z 607.07 [M+H]⁺.

n-Buthyllithium (1.6 M solution in THF, 2.07 mL, 3.32 mmol) was added toa solution of EtMgBr (1 M solution in THF, 1.66 mL, 1.66 mmol) in THF (5mL), which had been pre-cooled to 0° C. After 10 mins, the mixture wascooled to −78° C. A solution of 494-16 (1.00 g, 1.66 mmol) in THF (5 mL)was added dropwise, and the reaction was stirred at −78° C. for 15 mins.The reaction was quenched with MeOH and diluted with EtOAc. The organicportion was washed with brine, and the aqueous portion extracted withEtOAc. The combined organic portions were dried with Na₂SO₄, filteredand concentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 50:50 to 0:100) afforded 494-17 (775 mg, 70% purityA/A UV).

Dess-Martin periodinane (822 mg, 1.94 mmol) was added to a stirredsolution of 494-17 (775 mg) in DCM (7 mL). The reaction was stirred atr.t. for 2 h and quenched with a 1:1 mixture of 2M aq. Na₂S₂O₃ and sat.aq. NaHCO₃. After 20 mins of vigorous stirring, the layers wereseparated. The aqueous portion was extracted with DCM. The combinedorganic portions were dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,50:50 to 0:100) afforded 494-18 (480 mg, 60% over 2 steps).

Trimethylsulfoxonium iodide (57.5 mg, 0.261 mmol) was added in oneportion to a mixture of tBuOK (29.2 mg, 0.261 mmol) in CH₃CN (5 mL),which had been previously degassed. The mixture was further degassed andstirred at r.t. for 30 mins. The solution containing the ylide wasfiltered from the solid and added to a solution 494-18 (125 mg, 0.261mmol) in CH₃CN (4 mL), which had been previously degassed. The reactionwas stirred at r.t. for 15 mins. The volatiles were removed underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,80:20 to 0:100) afforded 494-19 as a colorless wax (51 mg, 40%).UPLC/MS(ES⁺): m/z 493.20 [M+H]⁺.

A solution of 494-19 (51 mg) in 7M NH₃-MeOH (30 mL) was stirred at r.t.for 18 h. The volatiles were removed under reduced pressure to afford494-20 (62 mg), which was directly in the next step.

A mixture of acid (0.136 mmol), HATU (51.7 mg, 0.136 mmol) and DIPEA (43uL, 0.246 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. Asolution of 494-20 (62 mg) in DCM (2 mL) was added, and the mixture wasstirred at r.t. for 1 h. The reaction was partitioned between DCM andwater, and the layers were separated. The organic portion was washedwith brine, dried with Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue afforded 494-21.

A 4M HCl-dioxane solution (1 mL) was added to a solution of 494-21(0.060 mmol) in MeOH (5 mL). After 30 mins, the volatiles were removedunder reduced pressure. The residue was purified by reverse phasechromatography to afford 494-22.

Coupling of 494-20 with 3-chloro-4-ethoxybenzoic acid followed byhydrolysis of the resulting sulfinamide afforded 494 (42% over 3 steps).UPLC/MS(ES⁺): m/z 588.20 [M+H]⁺.

Coupling of 494-20 with 4-ethoxy-3-methoxybenzoic acid followed byhydrolysis of the resulting sulfinamide afforded 498 (28% over threesteps). UPLC/MS(ES⁺): m/z 584.30 [M+H]⁺.

Coupling of 494-19 with 4-cyclopropoxy-3-methoxybenzoic acid afforded482 (68% over 2 steps). UPLC/MS(ES⁺): m/z 700.32 [M+H]⁺.

Hydrolysis of 482 according to general procedure afforded 483 as a whitesolid (formic acid salt, 76%). Alternatively, 483 was prepared by Suzukicoupling of 509-10A with 3-chloro-4-fluorophenylboronic acid andsubsequent hydrolysis of the resulting sulfinamide (53% over 2 steps).UPLC/MS(ES⁺): m/z 596.29 [M+H]⁺.

483 (100 mg) was resolved by prep-HPLC [Chiralpak AD-H (25×2 cm, 5 um),mobile phase: n-hexane/(ethanol+0.1% ipa) 80/20% v/v, flow rate: 14mL/min, UV detection DAD 220 nm]. Two fractions were recovered based onretention times: a mixture of 498a and 498b: 32 mg (t_(R)=14.3 min); anda mixture of 498c and 498d: 31 mg (t_(R)=19.0 min).

The mixture of 498a and 498b (32 mg) was resolved by prep-HPLC[Chiralcel OJ-H (25×2 cm, 5 um), mobile phase:n-hexane/(ethanol/methanol+0.1% ipa) 55/45% v/v, flow rate: 17 mL/min,UV detection DAD 220 nm]. Two fractions were recovered based onretention times: 498a: 9.3 mg (t_(R)=5.7 min). UPLC/MS(ES⁺): m/z 596.25[M+H]⁺; and 498b: 10.2 mg (t_(R)=8.8 min). UPLC/MS(ES⁺): m/z 596.25[M+H]⁺.

The mixture of 498c and 498d (31 mg) was resolved by prep-HPLC[Chiralpak IC (25×2 cm, 5 um), mobile phase: n-hexane/(2-propanol+0.1%ipa) 55/45% v/v, flow rate: 18 mL/min, UV detection DAD 220 nm]. Twofractions were recovered based on retention times: 498c: 10 mg(t_(R)=6.7 min). UPLC/MS(ES⁺): m/z 596.25 [M+H]⁺; and 498d: 8 mg(t_(R)=10.5 min). UPLC/MS(ES⁺): m/z 596.25 [M+H]⁺.

Example 259 Preparation of Compound 499

A solution of 483 (30 mg) and chloroacetaldehyde (50% aq. solution, 30uL) in MeOH (1.5 mL) was stirred at r.t. for 1 h. NaBH₃CN (2 mg) wasadded, and the mixture was stirred at r.t. for 18 h. The volatiles wereremoved under reduced pressure to afford a mixture of 499-1 andunreacted starting material (2:1), which was dissolved in DMF (1.5 mL).NaN₃ (10 mg) was added. The reaction was stirred at 70° C. for 20 h. Thevolatiles were removed under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 80:20 to 0:100) afforded 499-2 as a paleyellow oil (20 mg). UPLC/MS(ES⁺): m/z 665.30 [M+H]⁺.

A mixture of 499-2 (20 mg) and PPh₃ (10 mg) in 2:1 THF-H₂O (1.5 mL) wasstirred while heating to 60° C. for 2 h. The volatiles were removedunder reduced pressure. The residue was loaded on to an SCX column andeluted with 2M NH₃-MeOH to afford 499 (7 mg). UPLC/MS(ES⁺): m/z 639.30[M+H]⁺.

Example 260 Preparation of Compounds 530 and 531

Compounds 530 and 531 were prepared by using a strategy that follows theprocedure described for 509.

1-Bromo-2-butanone (300 mg, 1.98 mmol) was added to a solution of 509-3(1.00 g, 2.84 mmol) and potassium carbonate (520 mg, 4.26 mmol) inacetone (16.5 mL). The reaction was stirred at 50° C. for 1 h. Thevolatiles were removed under reduced pressure, and the residue waspartitioned between water and EtOAc. The layers were separated. Theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. The residue was triturated with DCM-cyclohexane toafford 530-1 as a white solid (1.02 g, 85%). UPLC/MS(ES⁺): m/z 423.93[M+H]⁺.

The reaction was performed in 2 batches. A mixture of 530-1 (510 mg,1.20 mmol), 2-methylpropane-2-sulfamide (160 mg, 1.32 mmol) andtitanium(IV) ethoxide (602 mg, 2.64 mmol) in THF (9.5 mL) was heated to70° C. (sealed vial, degassed and purged with N₂). The mixture wasstirred at 70° C. for 4 h. The 2 batches were unified, and EtOAc andwater were added. The mixture was filtered through a pad of celite. Thelayers were separated and the aqueous portion was extracted with EtOAc.The combined organic portions were dried with Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 95:5 to 60:40) afforded 530-2 (850 mg, 67%).UPLC/MS(ES⁺): m/z 527.00 [M+H]⁺.

EtMgBr (1M solution in THF, 1.61 mL, 1.61 mmol) was added to a solutionof n-BuLi (1.6M solution in THF, 2.01 mL, 3.23 mmol) in dry THF (5 mL),which had been pre-cooled to 0° C. After 30 mins, the mixture was cooledto −78° C. A solution of 530-2 (850 mg, 1.61 mmol) in dry THF (4 mL) wasadded dropwise, and the reaction was stirred at −78° C. for 20 mins. Thereaction was quenched with MeOH and diluted with EtOAc. The organicportion was washed with water and the aqueous portion extracted withEtOAc. The combined organic portions were dried with Na₂SO₄, filteredand concentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 30:70) afforded 530-3 as a white foam (441mg).

Dess-Martin periodinane (932 mg, 2.20 mmol) was added to a stirredsolution of 530-3 (441 mg) in DCM (5 mL). The reaction was stirred atr.t. for 1 h and quenched with a 1:1 mixture of 1M aq. Na₂S₂O₃ and 5%aq. NaHCO₃. After 20 min of vigorous stirring, the layers wereseparated. The aqueous portion was extracted with DCM. The combinedorganic portions were dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,100:0 to 0:100) afforded 530-4 as a white foam (320 mg, 50% over twosteps). UPLC/MS(ES⁺): m/z 417.10 [M+H₃O]⁺.

Trimethylsulfoxonium iodide (175 mg, 0.790 mmol) was added in oneportion to a mixture of tBuOK (88 mg, 0.790 mmol) in CH₃CN (15 mL),which had been previously degassed. The mixture was further degassed andstirred at r.t. for 30 mins. The solution containing the ylide wasfiltered from the solid and added to a solution 530-4 (317 mg, 0.790mmol) in CH₃CN (15 mL), which had been previously degassed. The reactionwas stirred at r.t. for 1 h. The volatiles were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to50:50) afforded 530-5 as a colorless wax (207 mg, 64%). UPLC/MS(ES⁺):m/z 413.12 [M+H]⁺.

A solution of 530-5 (207 mg) in 7M NH₃-MeOH (142 mL) was stirred at r.t.for 2 h. The volatiles were removed under reduced pressure to affordcrude 530-6 (203 mg) which was directly progressed to the next step.

A mixture of acid (0.233 mmol), HATU (86 mg, 0.252 mmol) and DIPEA (58uL, 0.336 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. Asolution of 530-6 (100 mg) in DCM (2 mL) was added. The mixture wasstirred at r.t. for 1 h. The reaction was partitioned between DCM andwater, and the layers were separated. The organic portion was washedwith brine, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by chromatography to give 530-7 or530-8.

A mixture of 530-7 or 530-8 (0.134 mmol), 4-fluorophenylboronic acid (38mg), K₃PO₄ (29 mg), KH₂PO₄ (18 mg) and Pd(dbpf)Cl₂ (17 mg) in aDME:EtOH:H₂O mixture (10:5:3, 3.6 mL) was degassed and warmed to 50°C.-70° C. DCM and water were added. The layers were separated. Theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by chromatography. A solutionof sulfamide (80 mg) in 4M HCl-dioxane was stirred at r.t. for 10 mins.The volatiles were removed under reduced pressure. The residue waspurified by reverse phase chromatography.

Coupling of 530-6 with 4-cyclopropoxy-3-methoxybenzoic acid afforded530-7, which was subjected to Suzuki coupling and sulfamide hydrolysisas described herein to afford 531 as a white solid (formic acid salt,25% overall). UPLC/MS(ES⁺): m/z 576.30 [M+H]⁺.

Coupling of 530-6 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3-methoxybenzoicacid afforded 530-8, which was subjected to Suzuki coupling andprotecting groups removal as described herein to afford 530 as a whitepowder (26% overall). UPLC/MS(ES⁺): m/z 580.34 [M+H]⁺.

Example 261 Preparation of Compounds 560, 565 and 568

Compounds 560, 565 and 531 were prepared by using a strategy thatfollows the procedure described for 509.

1-Bromo-3-methylbutan-2-one (659 mg, 3.99 mmol) was added to a solutionof 509-3 (2.01 g, 5.71 mmol) and potassium carbonate (1.18 g, 8.56 mmol)in acetone (34 mL). The reaction was stirred at 50° C. for 1 h. Thevolatiles were removed under reduced pressure and the residue waspartitioned between water and EtOAc. The layers were separated. Theorganic portion was dried with Na₂SO₄, filtered and concentrated underreduced pressure. The residue was tritured with cyclohexane and theprecipitate dried to afford 560-1 as a white solid (1.38 g, 55%).UPLC/MS(ES⁺): m/z 438.10 [M+H]⁺.

A mixture of 560-1 (1.38 g, 3.15 mmol), 2-methylpropane-2-sulfamide (419mg, 3.46 mmol) and titanium(IV) ethoxide (1.58 g, 6.93 mmol) in THF (25mL) was heated to 70° C. (sealed vial, degassed and purged with N₂) andstirred at 70° C. for 4 h. EtOAc and water were added. The mixture wasfiltered through a pad of celite. The layers were separated. The organicportion was dried with Na₂SO₄ and filtered. The volatiles were removedunder reduced pressure. Chromatography of the residue (cyclohexane:Et₂O,90:10 to 60:40) afforded 560-2 (841 mg, 50%). UPLC/MS(ES⁺): m/z 541.10[M+H]⁺.

n-Buthyllithium (1.6 M solution in THF, 1.93 mL, 3.10 mmol) was added toa solution of EtMgBr (1M solution in THF, 1.55 mL, 1.55 mmol) in THF (5mL), which had been pre-cooled to 0° C. After 10 mins, the mixture wascooled to −78° C. A solution of 560-2 (841 mg, 1.55 mmol) in THF (4 mL)was added dropwise and the reaction was stirred at −78° C. for 20 min.The reaction was quenched with MeOH and diluted with EtOAc. The organicportion was washed with brine and the aqueous portion extracted withEtOAc. The combined organic portions were dried with Na₂SO₄, filteredand concentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 30:70) afforded 560-3 as a white foam (580mg, 90%).

Dess-Martin periodinane (1.19 g, 2.80 mmol) was added to a stirredsolution of 560-3 (580 mg, 1.40 mmol) in DCM (10 mL). The reaction wasstirred at r.t. for 1 h and quenched with a 1:1 mixture of 2M aq.Na₂S₂O₃ and sat. aq. NaHCO₃. After 20 mins vigorous stirring, the layerswere separated. The aqueous portion was extracted with DCM. The combinedorganic portions were dried with Na₂SO₄, filtered and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,100:0 to 0:100) afforded 560-4 as a white foam (520 mg, 90%).

Trimethylsulfoxonium iodide (277 mg, 1.26 mmol) was added in one portionto a mixture of tBuOK (141 mg, 1.26 mmol) in CH₃CN (20 mL), which hadbeen previously degassed. The mixture was further degassed and stirredat r.t. for 30 mins. The solution containing the ylide was filtered fromthe solid and added to a solution 560-4 (520 mg, 1.26 mmol) in CH₃CN (20mL), which had been previously degassed. The reaction was stirred atroom temp for 15 min. Volatiles were removed under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 50:50)afforded 560-5 as a colorless oil (311 mg, 58%). UPLC/MS(ES⁺): m/z427.28 [M+H]⁺.

A solution of 560-5 (311 mg, 0.730 mmol) in 7M NH₃-MeOH (140 mL) wasstirred at r.t. for 2 h. The volatiles were removed under reducedpressure to afford 560-6 (313 mg), which was directly progressed to thenext step.

Method A: A mixture of 560-6 (155 mg, 0.350 mmol), acid (0.350 mmol),EDC (86.3 mg, 0.450 mmol), HOBT (61.4 mg, 0.450 mmol) and TEA (97 μL,0.700 mmol) in DCM (5 mL) was stirred at r.t. for 2 h. Water was addedand the mixture was stirred at r.t. for 10 mins. The layers wereseparated, and the organic portion was washed with brine, dried withNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof the residue (cyclohexane:EtOAc) afforded 560-7.

Method B: A mixture of acid (0.169 mmol), HATU (96.5 mg, 0.254 mmol),and DIPEA (59 uL, 0.338 mmol) in DMF (1 mL) was stirred at room temp for30 min. A solution of aminol 560-6 (100 mg) in DMF (1 mL) was added andthe reaction was stirred at room temp for 1 h. EtOAc was added and theorganic portion was washed twice with sat. aq. NH₄Cl solution, dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford560-7, which was directly progressed to the next step.

A mixture of 560-7 (0.250 mmol), 4-fluorophenylboronic acid (104 mg,0.740 mmol), K₃PO₄ (106 mg, 0.500 mmol), KH₂PO₄ (68 mg, 0.500 mmol) andPd(dbpf)Cl₂ (11 mg, 0.017 mmol) in a DME:EtOH:H₂O mixture (5:3:1, 18 mL)was degassed and warmed to 80° C. After 3 h, EtOAc was added. Theorganic portion was washed with sat. aq. NH₄Cl solution, dried withNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof the residue (cyclohexane:EtOAc) afforded 560-8.

Method A: Hydrochloric acid (4M solution in dioxane, 2 mL) was added toa solution of 560-8 (152 mg) in MeOH (4 mL). After 10 mins, thevolatiles were removed under reduced pressure. The residue was purifiedby reverse phase chromatography to afford 560-9.

Method B: A solution of 560-8 (0.089 mmol) in 4M HCl-dioxane (4 mL) wasstirred at r.t. for 40 mins. The volatiles were removed under reducedpressure. The residue was purified by reverse phase chromatography(water-CH₃CN, 100:0 to 50:50) to afford 560-9.

Coupling of 560-7 with 4-cyclopropoxy-3-methoxybenzoic acid according toMethod A afforded 560-8A (70%). UPLC/MS(ES⁺): m/z 634.33 [M+H]⁺.

Suzuki coupling of 560-8A with 4-fluorophenylboronic acid followed bysulfinamide hydrolysis (Method A) afforded 560 as a white solid (43%over 2 steps). UPLC/MS(ES⁺): m/z 590.40 [M+H]⁺.

Coupling of 560-7 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3-methoxybenzoicacid according to Method B afforded 560-8B which was progressed to thenext step without any purification.

Suzuki coupling of 560-8B with 4-fluorophenylboronic acid followed bysulfinamide hydrolysis (Method B) afforded 565 as an off-white solid(13% overall). UPLC/MS(ES⁺): m/z 594.40 [M+H]⁺.

Coupling of 560-7 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acidaccording to Method A afforded 560-8C (43%).

Suzuki coupling of 560-8C with 4-fluorophenylboronic acid followed bysulfinamide hydrolysis (Method A) afforded 568 (52% overall).UPLC/MS(ES⁺): m/z 608.50 [M+H]⁺.

Example 262 Preparation of Compounds 473, 474 and 475

Formaldehyde (37% aq. solution, 30.4 mL, 407 mmol) was added in 4portions to a mixture of 473-1 (15.0 g, 116 mmol) and NaHCO₃ (14.6 g,174 mmol) in water (120 mL) which had been pre-heated to 90° C. Thereaction was stirred at 90° C. for 16 h. Additional formaldehyde (37%aq. solution, 232 mmol) was added and the reaction was stirred at 90° C.for 1 h. After being cooled to r.t., the reaction was concentrated underreduced pressure. The crude 473-2 was directly used in the next step.

Iodine (25 g, 98.4 mmol) was added to a mixture of 473-2 (13 g) andK₂CO₃ (22.0 g, 159 mmol) in water (100 mL). The mixture was stirred atr.t. for 4 h. The reaction was poured in to a 1M aq. HCl solution, whichhad been pre-cooled to 0° C. The aqueous portion was extracted withEtOAc (3×). The combined organic portions were dried with Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 0:100)afforded 473-3 as an off-white solid (5.4 g). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 4.41 (s, 2H), 7.77 (s, 1H), 10.37 (s, 1H).

Chloroacetone (750 uL) was added to a mixture of 473-3 (2.41 g) andK₂CO₃ (1.69 g) in acetone (50 mL). The mixture was warmed to 50° C. andstirred at 50° C. for 16 h. The volatiles were removed under reducedpressure. The residue was partitioned between EtOAc and water. Thelayers were separated and the aqueous portion was extracted with EtOAc.The combined organic portions were dried with Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure. Trituration of theresidue with DCM:cyclohexane afforded 473-4 as a white solid (2.33 g).UPLC/MS(ES⁺): m/z 342.00 [M+H]⁺.

EtMgBr (1M solution in 2-methyltetrahydrofuran, 4.39 mL, 4.39 mmol) wasadded to a solution of n-BuLi (1.6 M solution in hexane, 5.48 mL, 8.78mmol) in THF (10 mL), which had been pre-cooled to 0° C. After 10 mins,the mixture was cooled to −78° C. A solution of 473-4 (1.35 g, 3.96mmol) in THF (8 mL) was added dropwise and the reaction was stirred at−78° C. for 2 h. The reaction was quenched with MeOH and diluted withEtOAc. The organic portion was washed with water, dried with Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 70:30 to 0:100) afforded 473-5 (619 mg,72%). UPLC/MS(ES⁺): m/z 216.10 [M+H]⁺.

Alcohol 473-5 was split in 2 batches (2×305 mg) which were separatelyprocessed as described below. The 2 reactions were unified for work-upand purification procedures. A mixture of 473-5 (305 mg, 1.42 mmol),(3-chloro-4-fluorophenyl)boronic acid (617 mg, 3.54 mmol), Pd(dppf)Cl₂(104 mg, 0.142 mmol) and sodium carbonate (2M aq. solution, 2.49 mL,5.00 mmol) in DCE (10 mL) was degassed and stirred with heating to 100°C. under microwave irradiation for 1.5 h. DCM and water were added. Thelayers were separated and the aqueous portion was extracted with DCM.The combined organic portions were dried with Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 50:50 to 0:100) afforded 473-6 (315 mg, 35%)and some unreacted 473-5 (94 mg). 473-6: ¹H NMR (400 MHz, CDCl₃) δ ppm1.74 (s, 3H), 4.48 (d, J=10.3 Hz, 1H), 4.66 (d, J=10.3 Hz, 1H), 4.75 (d,J=14.1 Hz, 1H), 4.79 (d, J=14.1 Hz, 1H), 7.22 (s, 1H), 7.23 (t, J=8.7Hz, 1H), 8.18 (ddd, J=8.7, 4.7, 2.3 Hz, 1H), 8.36 (dd, J=7.3, 2.3 Hz,1H).

Dess-Martin periodinane (365 mg, 0.861 mmol) was added to a stirredsolution of 473-6 (315 mg, 1.02 mmol) in DCM (5 mL). The reaction wasstirred at r.t. for 1.5 h. A 1:1 1M aq. Na₂S₂O₃:sat. aq. NaHCO₃ mixturewas added to the reaction and the mixture was stirred at r.t. for 20mins. The layers were separated and the aqueous portion was extractedwith DCM. The combined organic portions were dried with Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure.Chromatography of the residue (cyclohexane-EtOAc, 90:10 to 0:100)afforded 473-7 (266 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.57 (s,3H), 4.60 (d, J=10.3 Hz, 1H), 4.82 (d, J=10.3 Hz, 1H), 7.30 (t, J=8.7Hz, 1H), 8.02 (s, 1H), 8.32 (ddd, J=8.7, 4.6, 2.3 Hz, 1H), 8.50 (dd,J=7.3, 2.3 Hz, 1H), 10.11 (s, 1H).

Trimethylsulfoxonium iodide (191 mg, 0.866 mmol) was added to a solutionof tBuOK (97 mg, 0.866 mmol) in DMSO (3 mL). The mixture was stirred atr.t. for 30 mins. A solution of 473-7 (266 mg, 0.866 mmol) in DMSO (3mL) was added and the mixture was stirred at r.t. for 30 mins. Thereaction was diluted with EtOAc and water. The layers were separated andthe aqueous portion was extracted with EtOAc. The combined organicportions were washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 80:20 to 0:100) afforded 473-8 (81 mg, 29%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.75 (2×s, 3H), 3.00-3.04 (m, 1H), 3.24 (dd,J=5.1, 4.4 Hz, 1H), 4.11-4.15 (m, 1H) 4.48 (d, J=10.0 Hz, 1H), 4.68 (d,J=10.0 Hz, 1H), 7.20-7.28 (m, 2H), 8.21-8.28 (m, 1H), 8.40-8.46 (m, 1H).

A solution of 473-8 (81 mg, 0.252 mmol) in 7M NH₃-MeOH (50 mL) wasstirred at r.t. for 20 h. The volatiles were removed under reducedpressure. Crude 473-9 was directly used in to the next step.

A mixture of 4-cyclopropoxy-3-methoxybenzoic acid (63 mg, 0.302 mmol),HATU (144 mg, 0.378 mmol) and DIPEA (88 uL, 0.504 mmol) in DMF (1 mL)was stirred at r.t. for 30 mins. A solution of 473-9 in DMF (2 mL) wasadded and the mixture was stirred at r.t. for 1 h. EtOAc was added Theorganic portion was washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(EtOAc:MeOH, 100:0 to 80:20) afforded 473-10 (82 mg). UPLC/MS(ES⁺): m/z529.30 [M+H]⁺.

Dess-Martin periodinane (65 mg, 1.57 mmol) was added to a solution of473-10 (80 mg, 0.151 mmol) in DCM (5 mL). The reaction was stirred atr.t. for 10 mins. A 1:1 1M aq. Na₂S₂O₃:sat. aq. NaHCO₃ mixture wasadded. The mixture was stirred at r.t. for 20 mins. The layers wereseparated and the aqueous portion was extracted with DCM. The combinedorganic portions were dried with Na₂SO₄ and filtered. The volatiles wereremoved under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 70:30 to 0:100) afforded 473 (24 mg, 18% over 3steps) and 474 (19 mg, 15% over 3 steps). 473: white solid;UPLC/MS(ES⁺): m/z 527.30 [M+H]⁺. 474: off-white solid; UPLC/MS(ES⁺): m/z509.30 [M+H]⁺.

MeMgBr (3M solution in Et₂O, 30 uL, 0.090 mmol) was added to a solutionof 473 (16 mg, 0.030 mmol) in THF (2.5 mL). The reaction was stirred atr.t. under N₂ atmosphere for 30 mins. EtOAc and water were added. Thelayers were separated and the aqueous portion extracted with EtOAc. Thecombined organic portions were dried with Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 30:70 to 0:100) afforded 475 as a whitesolid (6 mg, 37%). UPLC/MS(ES⁺): m/z 543.30 [M+H]⁺.

Example 263 Preparation of Compounds 479 and 480

A mixture of 479-1 (1.00 g, 7.75 mmol), (4-fluorophenyl) boronic acid(2.17 g, 15.5 mmol), Pd(dppf)Cl₂ (566 mg, 0.775 mmol) and sodiumcarbonate (2M aq solution, 7.75 mL, 15.5 mmol) in DCE (70 mL) wasdegassed and stirred with heating to 85° C. overnight. Water and DCMwere added. The layers were separated and the organic phase wasconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-2 as a white solid (990mg, 67%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.16-7.29 (m, 3H), 7.34 (dd,J=8.2, 1.4 Hz, 1H), 8.04-8.12 (m, 2H), 8.15 (dd, J=4.4, 1.4 Hz, 1H),10.22 (s, 1H).

Potassium carbonate (1.15 g, 8.34 mmol) and trifluoroacetaldehyde ethylhemiacetal (740 uL, 6.26 mmol) were added to a suspension of 479-2 (790mg, 4.17 mmol) in water (15 mL). The mixture was stirred at 100° C.overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (327 uL,2.70 mmol) was added and the reaction was stirred at 100° C. overnight.The reaction was cooled to 0°, neutralized with 1M aq HCl solution andextracted with EtOAc. The organic portion was dried with Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-3 as a whitesolid (1.08 g, 90%). ¹H NMR (400 MHz, DMSO-de) δ ppm 5.00-5.14 (m, 1H),6.83 (d, J=6.3 Hz, 1H), 7.23-7.30 (m, 2H), 7.42 (s, 2H), 8.07-8.15 (m,2H), 10.48 (s, 1H).

NaH (195 mg, 4.87 mmol) was added to a stirred solution of 479-3 (1.08g, 3.75 mmol) in DMF (11 mL), which had been pre-cooled to 0° C. Themixture was stirred at 0° C. for 10 mins, then warmed to r.t. andstirred for 30 mins. The reaction was cooled to 0° C. andchloroacetonitrile (260 uL, 4.13 mmol) was added dropwise. The mixturewas allowed to gradually reach r.t. and stirring was continued for 20 h.EtOAc and sat. aq. NH₄Cl were added. The layers were separated. Theorganic portion was washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-4 as a colorless wax(1.10 g, 90%). ¹H NMR (400 MHz, DMSO-d) δ ppm 5.12-5.25 (m, 1H), 5.33(s, 2H), 7.02 (d, J=6.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.67 (d, J=8.7 Hz,1H), 7.83 (d, J=8.7 Hz, 1H), 7.91-7.98 (m, 2H).

LiAlH₄ (1M solution in THF, 3.17 mL, 3.17 mmol) was added dropwise to astirred solution of 479-4 (940 mg, 2.80 mmol) in THF (20 mL) which hadbeen pre-cooled to 0° C. The mixture was warmed to r.t. and stirred for30 mins. The reaction was cooled to 0° C. Water (3 mL) was slowly added,followed by 1N aq. NaOH solution (3 mL) and more water (9 mL). EtOAc wasthen added, and the layers were separated. The organic portion waswashed with brine, dried with Na₂SO₄, filtered and concentrated underreduced pressure. The crude 479-5 was directly used in the next step.

Di-tert-butyl dicarbonate (610 mg, 2.80 mmol) and DMAP (34.0 mg, 0.280mmol) were added to a solution of 479-5 in DCM (10 mL). After 2 h, waterwas added and the layers were separated. The organic portion was driedwith Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50)afforted a di-protected compound. This di-protected compound wasdissolved in CH₃CN (2 mL). A 1M aq. NaOH solution (2 mL) was added andthe reaction was stirred at 50° C. for 1 h. Most of the solvents wereremoved under reduced pressure and the pH of the resulting solution wasadjusted to 7 with 1M aq. HCl. The aqueous portion was extracted withEtOAc. The organic layer was dried with Na₂SO₄, filtered and evaporatedunder reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforted 479-6 as a white solid (235mg). UPLC/MS(ES⁺): m/z 431.38 [M+H]⁺.

Dess-Martin periodinane (274 mg, 0.640 mmol) was added to a stirredsolution of 479-6 (235 mg, 0.540 mmol) in DCM (9 mL). The reaction wasstirred at r.t. under N₂ atmosphere overnight and quenched with a 1:1 2Maq. Na₂S₂O₃:sat. aq. NaHCO₃ mixture. After 30 mins, the layers wereseparated. The organic portion was washed with brine, dried with Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-7 as a whitesolid (144 mg, 62%). UPLC/MS(ES⁺): m/z 447.29 [M+H₃O]⁺.

Trimethylsulfoxonium iodide (57.0 mg, 0.260 mmol) was added to asolution of tBuOK (29.0 mg, 0.260 mmol) in DMSO (3 mL). The mixture wasstirred at r.t. for 30 mins. A solution of 479-7 (112 mg, 0.260 mmol) inTHF (3 mL) was added, and the mixture was stirred at r.t. for 30 mins.The mixture was diluted with EtOAc and water, and the layers wereseparated. The aqueous layer was extracted with EtOAc. The combinedorganic portions were washed with brine, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-8 (44 mg) and unreacted479-7 (53 mg). 479-8: UPLC/MS(ES⁺): m/z 443.29 [M+H]⁺.

A solution of 479-8 (44 mg) in 7M NH₃-MeOH (2 mL) was stirred withheating to 45° C. for 40 mins. The volatiles were removed under reducedpressure. Crude 479-9 (45 mg) was directly used in the next step.

A mixture of 479-9 (45 mg), EDC (23 mg, 0.12 mmol), HOBT (17 mg, 0.12mmol), TEA (33 uL, 0.24 mmol) and 4-cyclopropoxy-3-methoxybenzoic acid(20 mg, 0.098 mmol) in DCM (1 mL) was stirred at r.t. for 2 h. Water wasadded, and the mixture was stirred for 10 mins. The layers wereseparated. The organic portion was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography (cyclohexane:EtOAc,100:0 to 40:60) afforded 479-10 as a white solid (53 mg). UPLC/MS(ES⁺):m/z 650.40 [M+H]⁺.

TFA (350 uL) was added to a solution of 479-10 (53 mg, 0.081 mmol) inDCM (2 mL). The mixture was stirred at r.t. for 30 mins. Water wasadded, and the layers were separated. The organic portion was dried withNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (water:CH₃CN, 100:0 to40:60) to afford 479 (A/1587/35/1) as a white solid (30 mg, 67%).UPLC/MS(ES⁺): m/z 550.32 [M+H]⁺.

Formaldehyde (37% aq. solution, 3 uL) was added to a solution of 479 (17mg, 0.030 mmol) in MeOH (200 uL). The mixture was stirred at r.t. for 3h. Sodium cyanoborohydride (1.8 mg, 0.030 mmol) was added, and thereaction was stirred at r.t. for 10 mins. The solvents were removedunder reduced pressure. Water and DCM were added. The layers wereseparated. The organic portion was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(DCM:MeOH, 100:0 to 90:10) afforded 480 as a white solid (2 mg, 10%).UPLC/MS(ES⁺): m/z 578.40 [M+H]⁺.

Example 264 Preparation of Compounds 506 and 507

LDA (2M solution, 39.4 mL, 78.7 mmol) was added to a solution of 507-1(5.00 g, 39.4 mmol) in dry THF (100 mL), which had been pre-cooled to−78° C. The mixture was stirred at −78° C. for 1 h. Dimethylcarbonate(8.0 mL, 95.0 mmol) was added, and the temperature was raised to 0° C.The reaction was stirred at 0° C. for 30 mins and then partitionedbetween EtOAc and sat. aq. NH₄Cl solution. The organic phase waspurified by chromatography (cyclohexane:EtOAc, 100:0 to 80:20) torecover 507-2 as a yellow oil (4.8 g, 66%).

Tetrakis(triphenylphosphine)-palladium(0) (1.18 g, 1.03 mmol) was addedto a mixture of 507-2 (3.8 g, 20.5 mmol), (4-fluorophenyl)boronic acid(4.30 g, 30.8 mmol) and Na₂CO₃ (5.4 g, 51.3 mmol) in 1:1 dioxane-H₂O (60mL), which had been previously degassed by bubbling N₂. The reaction wasstirred at 120° C. for 2 h. UPLC analysis of the reaction showed thatSuzuki coupling was followed by hydrolysis of the methyl ester. Themixture was concentrated under reduced pressure. The residue wasdissolved in MeOH and cone. H₂SO₄ was added. The reaction was warmed to50° C. and stirred at 50° C. for 2 h. EtOAc was added. The mixture wascooled to 0° C. and quenched with a sat. aq. K₂CO₃ (final pH 8). Thelayers were separated, and the organic portion was concentrated underreduced pressure. Chromatography of the residue (DCM:cyclohexane, 50:50)afforded 507-3 (2.66 g, 53%). UPLC/MS(ES⁺): m/z 246.20 [M+H]⁺.

LHMDS (1M solution in THF, 11.9 mL, 11.9 mmol) was added dropwise to asolution of 507-3 (2.66 g, 10.8 mmol) in THF (40 mL), which had beenpre-cooled to −78° C. The mixture was stirred at −78° C. for 1 h. Methyliodide (740 μL, 11.9 mmol) was added and the reaction was allowed togradually reach r.t. After being stirred at r.t. for 16 h, the reactionwas cooled to 0° C. and quenched with sat. aq. NaHCO₃ solution. Theaqueous portion was extracted with EtOAc. The organic layer wasconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 80:20) afforded 507-4 (1.70 g, 61%). UPLC/MS(ES⁺):m/z 260.10 [M+H]⁺.

LHMDS (1M solution in THF, 7.22 mL, 7.22 mmol) was added dropwise to asolution of 507-4 (1.70 g, 6.56 mmol) in THF (12 mL), which had beenpre-cooled to −78° C. The mixture was stirred at −78° C. for 1 h. Asolution of bromoacetonitrile (503 uL, 7.22 mmol) in THF (12 mL) wasadded, and the reaction was allowed to gradually reach r.t. After beingstirred at r.t. for 2 h, the reaction was cooled to 0° C. and quenchedwith sat. aq. NH₄Cl solution. The aqueous portion was extracted withEtOAc. The organic layer was concentrated under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 50:50) afforded 507-5(1.91 g, 98%). ¹H NMR (400 MHz, DMSO-d₆) d ppm 1.76 (s, 3H), 3.37 (d,J=17.0 Hz, 1H), 3.44 (d, J=17.0 Hz, 1H), 3.72 (s, 3H), 7.31-7.40 (m,3H), 7.90 (d, J=1.5 Hz, 1H), 8.15-8.23 (m, 2H), 8.68 (d, J=53 Hz, 1H).

Nickel Raney (0.600 mmol) was added to a solution of 507-5 (1.91 g, 6.40mmol) in MeOH (50 mL). The reaction was stirred at 60° C. under H₂atmosphere (5 bar) for 3 h. The reaction was filtered through a pad ofcelite and the solution was refluxed for 4 h. DIPEA (1 eq.) was added,and the mixture was refluxed for 30 mins. The volatiles were removedunder reduced pressure. The residue was dissolved in EtOAc. The organicportion was washed with sat. aq. NaHCO₃ solution, dried and concentratedunder reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0to 95:5) afforded 507-6 (870 mg, 50%). UPLC/MS(ES⁺): m/z 271.20 [M+H]⁺.

LiAlH₄ (2M solution in THF, 3.03 mL, 6.06 mmol) was added to a solutionof 507-6 (820 mg, 3.03 mmol) in THF (18 mL), which had been pre-cooledto 0° C. The reaction was stirred at r.t. for 1 h, then warmed to 70° C.and stirred at 70° C. for 30 mins. The reaction was cooled to 0° C. andNa₂SO₄.10 H₂O and Et₂O were added. The mixture was filtered through apad of celite, and the solution concentrated under reduced pressure.Crude 507-7 (720 mg) was directly used in the next step.

A mixture of 507-7 (720 mg) and sat. aq. NaHCO₃ solution (16 mL) indioxane (9 mL) was cooled to 0° C. A solution of FmocCl (764 mg, 2.95mmol) in dioxane (9 mL) was added, and the reaction was allowed to reachr.t. After 1 h, the reaction was diluted with EtOAc. The organic portionwas washed with water and brine, dried and concentrated under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50)afforded 507-8 (1.10 g, 49% over 2 steps). UPLC/MS(ES⁺): m/z 479.40[M+H]⁺.

m-Chloroperbenzoic acid (797 mg, 4.62 mmol) was added to a solution of507-8 (1.10 g, 2.31 mmol) in DCM (30 mL). The reaction was stirred atr.t. overnight. EtOAc was added. The organic phase was washed with sat.aq. K₂CO₃ sol and concentrated under reduced pressure. Crude 507-9 (1.17g) was directly used in the next step.

A mixture of 507-9 (1.17 g) and POCl₃ (50 mL) was stirred at 60° C. for12 h. The volatiles were removed under reduced pressure. EtOAc and waterwere added, and the mixture was basified by adding sat. aq. KHCO₃solution (final pH 8). The layers were separated, and the organicportion was concentrated under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 90:10 to 0:100, then EtOAc:MeOH, 80:20)afforded 507-10 (700 mg, 58%) and unreacted starting material 507-9 (300mg). 507-10: UPLC/MS(ES⁺): m/z 513.27 [M+H]⁺.

Tributyl[1-ethoxyethenyl]stannane (552 uL, 1.63 mmol) and Pd(PPh₃)Cl₂(199 mg, 0.284 mmol) were sequentially added to a solution of 507-10(700 mg, 1.36 mmol) in dioxane (4 mL), which had been previouslydegassed by bubbling N₂. The mixture was further degassed and stirred at100° C. for 1 h. After being cooled to r.t., the mixture was partitionedbetween EtOAc and sat. aq. KF solution. The layers were separated. Theorganic portion was washed with 1M aq. HCl solution, dried andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 80:20) afforded 507-11 (670 mg, 95%). UPLC/MS(ES⁺):m/z 521.32 [M+H]⁺.

Hydrobromic acid (33% solution in AcOH, 377 uL, 2.08 mmol) and bromine(53 uL, 1.04 mmol) were added to a solution of 507-11 (541 mg, 1.04mmol) in dioxane (10 mL), which had been pre-cooled to 0° C. Thereaction was stirred at r.t. for 2 h. Additional bromine (0.5 eq., 27μL) was added and stirring was prolonged for 2 h. The reaction wasquenched with water and neutralized with sat. aq. NaHCO₃ solution. Theaqueous portion was extracted with DCM. The organic layer was dried withNa₂SO₄ and concentrated under reduced pressure. Chromatography of theresidue (DCM:EtOAc, 60:40) afforded 507-12.

TMSCF₃ (430 mg, 3.00 mmol) and CsF (91 mg) were sequentially added to asolution of 507-12 (90 mg) in THF (12 mL). The reaction was stirred atr.t. for 20 mins. The mixture was partitioned between EtOAc and 1M aq.HCl solution. The layers were separated, and the organic portion wasconcentrated under reduced pressure. Crude 507-13 was directly used inthe next step.

A solution of 507-13 in ammonia (7M solution in MeOH, 5 mL) was stirredat r.t. for 1.5 h. The volatiles were removed under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc-MeOH, 60:30:10)afforded 507-14 (44 mg). UPLC/MS(ES⁺): m/z 606.40 [M+H]⁺.

A solution of 4-cyclopropoxy-3-methoxybenzoic acid (20.0 mg, 0.095mmol), DIPEA (50 uL, 0.270 mmol) and HATU (39.0 mg, 0.102 mmol) in DCM(4 mL) was stirred at r.t. for 30 mins. A solution of 507-14 (41.0 mg,0.068 mmol) in DCM (1 mL) was added. The reaction was stirred for 16 h,quenched with MeOH (10 mL) and stirred for 1 h. The volatiles wereremoved under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 60:40) afforded 507-15 as a colorless oil(23 mg, 42%). UPLC/MS(ES⁺): m/z 796.50 [M+H]⁺.

Morpholine (1 mL) was added to a solution of 507-15 (23 mg, 0.029 mmol)in DMF (1 mL), and the solution was stirred for 1 h. The volatiles wereremoved under reduced pressure. Chromatography of the residue(NH-cartridge, cyclohexane:EtOAc:MeOH, 100:0:0 to 60:30:10) afforded 507(10 mg, 60%). UPLC/MS(ES⁺): m/z 574.30 [M+H]⁺.

Formaldehyde (37% aq. solution, 30 uL, 0.350 mmol) and NaBH(OAc)₃ (22.0mg, 0.105 mmol) were added to a solution of 507 (4.0 mg, 0.007 mmol) inDCM (2 mL). The reaction was vigorously stirred overnight, quenched with1M aq. NaOH solution and extracted with DCM. The volatiles were removedunder reduced pressure. The residue was purified by SCX-chromatographyto afford 506 as a colorless oil (2.4 mg, 58%). UPLC/MS(ES⁺): m/z 588.50[M+H]⁺.

Example 265 Preparation of Compounds 519, 520, 521, 527 and 523

General Suzuki Coupling Conditions

Method A: A mixture of 519-1 (70 mg, 0.112 mmol), boronate/boronic acid(0.170 mmol), KH₂PO₄ (15.3 mg, 0.112 mmol), K₃PO₄ (24.0 mg, 0.112 mmol)and Pd(dbpf)Cl₂ (7.5 mg, 0.011 mmol) in DME:H₂O:EtOH (1:0.5:0.3, 1.8 mL)was degassed and heated to 50° C. for 24 h. The mixture was partitionedbetween Et₂O and water. The organic portion was concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc)afforded 519-2.

Method B: A mixture of 519-1 (90 mg, 0.145 mmol), boronic acid (0.322mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), PCy₃ (10 mg, 0.038 mmol) and K₃PO₄(85 mg, 0.402 mmol) in dioxane (1 mL)-water (300 uL) was degassed andheated to 100° C. for 12 h. The volatiles were removed under reducedpressure. Chromatography of the residue (cyclohexane:EtOAc) afforded519-2.

Protecting Group(s)-Removal:

Method A: Aqueous HCl (6M solution, 4 mL) was added to a solution of519-2 (0.056 mmol) in isopropanol (2.5 mL). The reaction was heated to95° C. for 3 h. The volatiles were removed under reduced pressure. Theresidue was purified by reverse phase chromatography to afford 519-3.

Method B: A mixture of 519-2 (0.047 mmol) and Pd/C (9 mg) in MeOH (4.7mL) was stirred under H₂ atmosphere for 5 h. The mixture was filteredfrom the catalyst, and the solution was treated with 1M HCl solution inEt₂O. The volatiles were removed under reduced pressure. The residue wastriturated with Et₂O to afford 519-3 as its hydrochloride salt.

Method C: TMSCl (32 uL) and NaI (39 mg) were sequentially added to asolution of 519-2 (0.089 mmol) in CH₃CN (4 mL). The reaction was stirredat r.t. for 1 h, warmed to 45° C. and stirred at that temp for 16 h.Additional TMSCl (64 uL) and NaI (80 mg) were added, and the reactionwas stirred at 45° C. for 5 h. The volatiles were removed under reducedpressure. The residue was partitioned between EtOAc and a 1:1 mixture of5% aq. NaHCO₃:1M aq. Na₂S₂O₃. The layers were separated, and the aqueousportion was extracted with EtOAc. The combined organic portions weredried with Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography to give 519-3.

Method D: Hydrobromic acid (33% solution in AcOH, 30 uL) was added to asolution of 519-2 (20 mg) in 4M HCl-dioxane (2 mL). The reaction waswarmed to 70° C. When complete Cbz-removal was observed by UPLC, thereaction was concentrated under reduced pressure. The residue purifiedby reverse phase chromatography to afford 519-3.

Method E: A mixture of 519-2 (9.1 mg) in 4M HCl-dioxane (2 mL) waswarmed to 70° C. (or 100° C.). When complete Cbz-removal was observed byUPLC, the reaction was concentrated under reduced pressure, and theresidue purified by reverse phase chromatography to afford 519-3,

Suzuki coupling of 519-1 with1-((2-(trimethylsilyl)ethoxy)methyl)-7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(Method A) followed by protecting groups removal according to Method Aafforded 519 as its hydrochloride salt (white solid, 16% overall).UPLC/MS(ES⁺): m/z 587.36 [M+H]⁺.

Suzuki coupling of 519-1 with 4-chlorophenylboronic acid (Method A)followed by Cbz-removal according to Method A afforded 520 as itshydrochloride salt (white solid, 24% overall). UPLC/MS(ES⁺): m/z 564.30[M+H]⁺.

Suzuki coupling of 519-1 with 4-fluoro-3-(trifluoromethyl)phenylboronicacid (Method A) followed by Cbz-removal according to Method B afforded521 as its hydrochloride salt (45% overall). UPLC/MS(ES⁺): m/z 616.38[M+H]⁺.

Suzuki coupling of 519-1 with 4-cyanophenylboronic acid (Method A)followed by Cbz-removal according to Method C afforded 527 as its formicacid salt (white solid, 37% overall). UPLC/MS(ES⁺): m/z 555.40 [M+H]⁺.

Suzuki coupling of 519-1 with 4-(trifluoromethyl)phenylboronic acid(Method A) followed by Cbz-removal according to Method B afforded 523(5% overall). UPLC/MS(ES⁺): m/z 598.30 [M+H]⁺.

Example 266 Preparation of Compound 524

Suzuki coupling of 519-1 (310 mg) with2-(4-fluoro-3-nitrophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (Method A ofExample 265) afforded 519-2A (35 mg). UPLC/MS(ES⁺): m/z 727.30 [M+H]⁺.

Iron powder (8 mg, 0.144 mmol) was added to a solution of 519-2A (35 mg,0.05 mmol) in 2:2:1 EtOH:AcOH—H₂O (2.5 mL). The mixture was heated to80° C. for 1 h. The reaction was filtered through a pad of celite, andthe volatiles were evaporated under reduced pressure. The crude waspartitioned between EtOAc and aq. NaHCO₃ solution, and the organicportion was purified by chromatography to afford 519-4 (30 mg).UPLC/MS(ES⁺): m/z 697.40 [M+H]⁺.

Aniline 519-4 (30 mg) was dissolved in CH₃CN (2 mL) under N2 atmosphere.t-BuONO (14 mg, 0.129 mmol) was added. The mixture was stirred at r.t.for 30 mins. CuBr (6.2 mg, 0.043 mmol) was added, and the mixture wasstirred for 2.5 h. The reaction was partitioned between DCM and sat. aq.NH₄Cl solution. The organic phase was purified by chromatography torecover 519-5 (12 mg).

Deprotection of 519-5 according to Method A of Example 265 afforded 524as its hydrochloride salt (1.2 mg). UPLC/MS(ES⁺): m/z 626.30 [M+H]⁺.

Example 267 Preparation of Compounds 557 and 567

Suzuki coupling of 519-1 with 2-chloropyridine-5-boronic acid (Method Bof Example 265) followed by treatment of the resulting Cbz-protectedamine with TMSCl/NaI according to Method C of Example 265 afforded 557(5% overall). UPLC/MS(ES+): m/z found 657.32 [M+H]⁺.

Deprotection of 519-2B according to Method E of Example 265 afforded 567(16%). UPLC/MS(ES⁺): m/z 565.40 [M+H]⁺.

Example 268 Preparation of Compound 558

Suzuki coupling of 519-1 with 2-chloropyridine-4-boronic acid (Method Bof Example 265) followed by Cbz-removal according to Method D of Example265 afforded 558 (3% overall). UPLC/MS(ES⁺): m/z 565.30 [M+H]⁺.

Example 269 Preparation of Compound 559

Suzuki coupling of 519-1 with 3-cyano-4-fluorophenylboronic acid (MethodA of Example 265) followed by Cbz-removal according to Method D ofExample 265 afforded 559 (10% overall). UPLC/MS(ES⁺): m/z 573.42 [M+H]⁺.

Example 270 Preparation of Compound 514

NaBH₄ (808 mg, 21.3 mmol) was added to a solution of 514-1 (3.10 g, 17.7mmol) in MeOH (22 mL), which had been pre-cooled to 0° C. The mixturewas allowed to reach r.t. and stirring was prolonged for 30 mins. 1M aq.HCl solution was added, and the organic solvent was removed underreduced pressure. The aqueous phase was extracted with DCM (3×). Thecombined organic portions were dried with Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure to afford 514-2 (3.01 g).UPLC/MS(ES⁺): m/z 178.00 [M+H]⁺.

Chloromethyl methyl ether (704 μL, 9.27 mmol) and TEA (1.75 mL, 12.6mmol) were added to a solution of 514-2 (1.5 g) in DCM (12 mL). Thereaction was warmed to 45° C. When complete conversion was observed byUPLC, the reaction was cooled to r.t., diluted with DCM and washed withwater. The organic portion was concentrated under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 70:30) afforded 514-3(1.48 g). UPLC/MS(ES⁺): m/z 222.00 [M+H]⁺.

A mixture of 514-3 (1.38 g, 6.24 mmol), Pd(PPh₃)Cl₂ (438 mg, 0.624 mmol)and tributyl[1-ethoxyethenyl]stannane (2.11 mL, 6.24 mmol) in dioxane(40 mL) was degassed, warmed to 90° C. and stirred at that temp for 3 h.After being cooled to r.t., the reaction was diluted with EtOAc. Theorganic portion was washed with a sat. aq. KF solution and water, driedwith Na₂SO₄, filtered and concentrated under reduced pressure to affordcrude 514-4, which was directly used in the next step.

NBS (888 mg, 4.99 mmol) was added to a solution of 514-4 in THF (40 mL),which had been pre-cooled to 0° C. The reaction was stirred at 0° C. for1 h, then warmed to r.t., and stirred for 2 h. EtOAc was added. Theorganic portion was washed with water, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 70:30) afforded 514-5 (1.11 g).

CF₃TMS (6 mL) was added to a solution of 514-5 (1.11 g) in THF (15 mL).CsF (2.74 g, 18.0 mmol) was added in 1 portion. After 1 h, the reactionwas partitioned between EtOAc and sat. aq. NH₄Cl solution. The layerswere separated, and the aqueous portion was extracted with EtOAc. Thecombined organic portions were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. Crude 514-6 was directly used inthe next step.

A solution of 514-6 and 7M NH₃-MeOH (50 mL) was stirred at r.t. for 16h. The volatiles were removed under reduced pressure. The residue waspurified by reverse phase chromatography (water:CH₃CN, 100:0 to 50:50)to afford 514-7 (214 mg). UPLC/MS(ES⁺): m/z 315.30 [M+H]⁺.

A mixture of 514-7 (291 mg, 0.928 mmol), EDC (212 mg, 1.11 mmol), HOBT(150 mg, 1.11 mmol), TEA (310 uL, 2.23 mmol) and4-cyclopropoxy-3-methoxybenzoic acid (193 mg, 0.924 mmol) in DCM (6 mL)was stirred at r.t. for 2 h. A 1M aq. HCl solution was added, and themixture was stirred for 2 mins. The layers were separated. The organicportion was washed with 1M aq. NaOH solution, and concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,70:30) afforded 514-8 (140 mg, 30%). UPLC/MS(ES⁺): m/z 505.20 [M+H]⁺.

A mixture of 514-8 (67.6 mg, 0.134 mmol), 4-fluorophenylboronic acid (28mg, 0.201 mmol), KH₂PO₄ (21 mg, 0.134 mmol), K₃PO₄ (29.0 mg, 0.134 mmol)and Pd(dbpf)Cl₂ (9 mg, 0.013 mmol) in DME-H₂O-EtOH (5:3:1, 5 mL) wasdegassed and heated to 50° C. for 48 h. The mixture was partitionedbetween DCM and water. The organic portion was concentrated underreduced pressure. Chromatography of the residue (cyclohexane:EtOAc,70:30) afforded 514-9 (50.7 mg). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.80-0.90(m, 4H), 3.36 (s, 3H), 3.72-3.81 (m, 1H), 3.85 (s, 3H), 3.97 (dd,J=14.0, 3.5 Hz, 1H), 4.58 (s, 2H), 4.62-4.73 (m, 3H), 6.43 (dd, J=7.9,3.5 Hz, 1H), 6.67 (s, 1H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 7.14-7.22 (m,3H), 7.25 (d, J=1.8 Hz, 1H), 7.53-7.61 (m, 2H), 7.78 (d, J=8.1 Hz, 1H),8.05 (d, J=8.1 Hz, 1H).

A solution of 514-9 (50.7 mg, 0.09 mmol) in 1:1 DCM-TFA (700 μL) wasstirred at r.t. for 12 h. The reaction was diluted with DCM. The organicportion was washed with 2M aq. NaOH solution and concentrated underreduced pressure. Crude 514-10 (45 mg) was directly used in the nextstep. UPLC/MS(ES⁺): m/z 521.30 [M+H]⁺.

TEA (19 μL, 0.136 mmol) and MsCl (10 μL, 0.133 mL) were sequentiallyadded to a solution of 514-10 (45 mg) in DCM (1 mL), which had beenpre-cooled to 0° C. The reaction was allowed to reach r.t., stirred for12 h and diluted with DCM. The organic portion was washed with water,dried with Na₂SO₄, filtered and concentrated under reduced pressure.Crude 514-11 (36 mg) was directly used in the next step.

A solution of 514-11 (36 mg) in 7M NH₃-MeOH (1 mL) was stirred at r.t.for 12 h. The volatiles were removed under reduced pressure. The residuewas purified by reverse phase chromatography (water:CH₃CN, 100:0 to67:33) to afford 514 (19.6 mg). UPLC/MS(ES⁺): m/z 520.30 [M+H]⁺.

Example 271 Preparation of Compound 538

A 0.2 M solution of 538-1 (465 mg, 1.14 mmol) in toluene (5.7 mL) wasdegassed (mw vial). Pd(Q-phos)₂ (80 mg, 0.052 mmol) was added. The vialwas sealed, purged with N2 and heated to 100° C. for 6 h. AdditionalPd(Q-phos)₂ (30 mg) was added. The vial was purged with N₂ and heated to100° C. for 4 h. The mixture was directly purified by chromatography onsilica gel (cyclohexane:EtOAc, 95:5 to 70:30) to afford 538-2 (414 mg,96%). UPLC/MS(ES⁺): m/z 408.10 [M+H]⁺.

A mixture of 538-2 (340 mg) and NaN₃ (288 mg) in DMF (4 mL) was heatedto 65° C. and stirred at that temp for 16 h. The volatiles were removedunder reduced pressure. The crude residue was partitioned between EtOAcand sat. aq. NH₄Cl solution. The layers were separate. The organicportion was dried with Na₂SO₄, filtered and concentrated under reducedpressure to afford 538-3 (245 mg). UPLC/MS(ES⁺): m/z 323.10 [M+H]⁺.

Dess-Martin periodinane (484 mg, 1.14 mmol) was added to a solution of538-3 (245 mg) in DCM (4 mL). The reaction was stirred at r.t. for 1 hand quenched with a 1:1 1M aq. Na₂S₂O₃:5% aq. NaHCO₃. The mixture wasvigorously stirred for 1 h. The layers were separated, and the aqueousportion was extracted with DCM. The combined organic portions were driedwith Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc) afforded 538-4 (206mg). UPLC/MS(ES⁺): m/z 339.10 [M+H₃O]⁺.

Trimethylsulfoxonium iodide (141 mg, 0.643 mmol) was added in oneportion to a mixture of tBuOK (72 mg, 0.643 mg) in CH₃CN (4 mL), whichhad been previously degassed. After 20 mins, the solution was filteredfrom the solid and added to a solution of 538-4 (206 mg) in CH₃CN (4mL), which had been previously degassed. The reaction was stirred atr.t. for 15 mins. The volatiles were removed under reduced pressure.Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50)afforded 538-5. UPLC/MS(ES⁺): m/z 335.10 [M+H]⁺.

A solution of 538-5 (100 mg) in 7M NH₃-MeOH (60 mL) was stirred at r.t.for 1 h. The volatiles were removed under reduced pressure to affordcrude 538-6 (108 mg), which was directly used in the next step.UPLC/MS(ES⁺): m/z 352.10 [M+H]⁺.

A mixture of 538-6 (108 mg), EDC (89 mg, 0.462 mmol), HOBT (63 mg, 0.462mmol), 4-cyclopropoxy-3-methoxybenzoic acid (64 mg, 0.307 mmol) and TEA(86 uL, 0.616 mmol) in DCM (4 mL) was stirred at r.t. for 16 h. Thereaction was diluted with DCM. The organic portion was washed with 1Maq. HCl solution (2×), dried with Na₂SO₄, filtered and concentratedunder reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 50:50) afforded 538-7 (136 mg).UPLC/MS(ES⁺): m/z 542.20 [M+H]⁺.

Pd(dbpf)Cl₂ (16 mg, 0.025 mmol) was added to a mixture of 538-7 (136mg), K₃PO₄ (107 mg, 0.503 mmol), KH₂PO₄ (68 mg, 0.503 mg) and4-fluorophenylboronic acid (74 mg, 0.503 mmol) in 5:3:1 DME:EtOH:H₂O(2.7 mL), which had been previously degassed. The reaction was warmed to65° C. and stirred at that temp for 10 h. The mixture was cooled to r.t.and stirred for 72 h. The reaction was diluted with EtOAc and washedwith sat. aq. NH₄Cl solution. The organic portion was dried with Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (water/0.1% HCOOH:CH₃CN/0.1%HCOOH, 100:0 to 50:50) to afford 538 as a white solid (formic acid salt,33 mg, dr 1:1). UPLC/MS(ES⁺): m/z 576.40 [M+H]⁺.

Example 272 Preparation of Compound 522

meta-Chloroperbenzoic acid (56.0 g, 328 mmol) was added in severalportions to a solution of 2-chloro-4-methylpyridine (20.0 g, 156 mmol)in DCM (520 mL). The mixture was refluxed for 8 h and diluted with DCM.The organic portion was washed with sat. aq. K₂CO₃ solution. The aqueousportion was extracted with EtOAc. The combined organic portions weredried with Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue (DCM:MeOH, 100:0 to 80:20) afforded 522-1as a yellow oil (9.50 g, 42%). UPLC/MS(ES⁺): m/z 144.00 [M+H]⁺.

POCl₃ (130 mL) was added to a solution of 522-1 (9.50 g, 66.0 mmol) intoluene (20 mL). The reaction was heated to 70° C. and stirred at thattemp for 20 h. The volatiles were removed under reduced pressure. Theresidue was poured into ice. The mixture neutralized with sat. aq. K₂CO₃solution and extracted with DCM (3×). The combined organic portions weredried with Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue afforded 522-2 (3.80 g, 36%).UPLC/MS(ES⁺): m/z 162.10 [M+H]⁺.

A freshly prepared solution of LDA solution (1M in THF-hexane, 44.6 mL,44.6 mmol) was added to a solution of 522-2 (3.61 g, 22.3 mmol) in THF(110 mL), which had been pre-cooled to −78° C. The reaction was stirredat −78° C. for 1 h. Dimethylcarbonate (4.5 mL, 53.5 mmol) was added. Thereaction was allowed to reach 0° C., stirred at that temp for 1 h andquenched with water. The volatiles removed under reduced pressure. Theresidue was taken up with EtOAc. The organic portion was washed withsat. aq. NH₄Cl solution, dried with Na₂SO₄, filtered and concentratedunder reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 100:0 to 60:40) afforded 522-3 as a yellow oil (3.0g, 61%). UPLC/MS(ES⁺): m/z 220.0 [M+H]⁺.

A mixture of 522-3 (450 mg, 2.00 mmol), 3-chloro-4-fluorophenylboronicacid (285 mg, 1.60 mmol), NaHCO₃ (515 mg, 6.10 mmol) and Pd(PPh₃)₄ (95mg, 0.080 mmol) in 2:1 THF:water (9 mL) was degassed and heated to 50°C. After 2 h, 3-chloro-4-fluorophenyl boronic acid (0.2 eq.) was added,and the mixture was stirred at 50° C. for 2 h. After being cooled tor.t., the reaction was diluted with DCM. The organic portion was washedwith sat. aq. NaHCO₃ solution, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (water:CH₃CN, 70:30 to 10:90) to afford 522-4 as ayellow oil (180 mg, 29%). UPLC/MS(ES⁺): m/z 314.10 [M+H]⁺.

522-4 (860 mg, 2.70 mmol) was dissolved in 7M NH₃-MeOH (14 mL) at 0° C.The reaction was stirred at r.t. for 3 h and at 40° C. for 20 h. Thevolatiles were removed under reduced pressure to afford crude 522-5 (775mg), which was directly used in the next step.

Borane-THF complex (1M solution in THF, 7.77 mL, 7.77 mmol) was added toa solution of 522-5 (775 mg) in THF (14 mL). The reaction was refluxedfor 3 h. Additional borane-THF complex (4 eq., 2 aliquots) was added,and the mixture was refluxed overnight. The reaction was quenched with2M aq. HCl solution, and the mixture was stirred for 30 mins. Theaqueous portion was basified with sat. aq. NaHCO₃ solution and extractedwith EtOAc. The organic portion was washed with brine, dried withNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas loaded on to a SCX-column and eluted with 2M NH₃-MeOH to give 522-6(610 mg, 82%). UPLC/MS(ES⁺): m/z 285.10 [M+H]⁺.

Triethylamine (590 uL, 4.26 mmol) and Boc₂O (700 mg, 3.20 mmol) weresequentially added to a solution of 522-6 (610 mg, 2.13 mmol) in DCM (11mL). The reaction was stirred at r.t. for 1 h, diluted with DCM andwashed with 0.5M aq. HCl solution. The organic portion was dried withNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof the residue (cyclohexane:EtOAc, 90:10 to 50:50) afforded 522-7 as awhite solid (580 mg, 71%). UPLC/MS(ES⁺): m/z 385.20 [M+H]⁺.

A mixture of 522-7 (580 mg, 1.50 mmol), Pd(PPh₃)Cl₂ (105 mg, 0.150 mmol)and tributyl[1-ethoxyethenyl]stannane (560 uL, 1.65 mmol) in dioxane (8mL) was degassed, warmed to 100° C. and stirred at that temp for 6 h.After being cooled to r.t., a sat. aq. KF solution was added. Themixture was stirred for 10 mins, and the aqueous portion was extractedwith EtOAc. The organic phase was dried with Na₂SO₄, filtered andconcentrated under reduced pressure to afford crude 522-8, which wasdirectly used in the next step.

A-Bromosuccinimide (293 mg, 1.65 mmol) was added to a solution of 522-8in THF (8 mL), which had been pre-cooled to 0° C. The reaction wasstirred at 0° C. for 1 h, quenched with water and extracted with EtOAc.The organic portion was dried with Na₂SO₄, filtered and concentratedunder reduced pressure. Chromatography of the residue(cyclohexane:EtOAc, 90:10 to 50:50) afforded 522-9 as a white solid (330mg, 47% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 9H), 3.00(t, J=6.5 Hz, 2H), 3.50 (q, J=6.5 Hz, 2H), 4.58-4.69 (m, 1H), 4.95 (s,2H), 7.30 (t, J=8.0 Hz, 1H), 7.79 (br. s., 1H), 7.92 (s, 1H), 7.95-8.02(m, 1H), 8.15 (dd, J=6.9, 2.1 Hz, 1H).

CF₃TMS (1.03 mL, 7.00 mmol) was added to a solution of 522-9 (330 mg,0.700 mmol) in THF (5 mL). CsF (531 mg, 3.50 mmol) was added in oneportion. After 1 h, the reaction was partitioned between EtOAc and sat.aq. NH₄Cl solution. The layers were separated, and the aqueous portionwas extracted with EtOAc. The combined organic portions were dried withNa₂SO₄, filtered and concentrated under reduced pressure. The crude522-10 was directly used in the next step.

A solution of 522-10 and 7M NH₃-MeOH (10 mL) was stirred at r.t. for 3h. The volatiles were removed under reduced pressure. The residue waspurified by reverse phase chromatography (water:CH₃CN, 95:5 to 30:70) toafford 522-11 (56 mg).

A mixture of 4-cyclopropoxy-3-methoxybenzoic acid (49.0 mg, 0.230 mmol),HATU (108 mg, 0.280 mmol) and DIPEA (122 uL, 0.700 mmol) in DCM (1 mL)was stirred at r.t. for 30 mins. A solution of 522-11 (56 mg) in DCM (1mL) was added, and the reaction was stirred at r.t. for 2 h and quenchedwith water. EtOAc was added. The organic portion was washed with 1M aq.HCl solution, 2M aq. NaOH solution and brine, dried with Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography of theresidue (cyclohexane:EtOAc, 90:10 to 40:60) afforded 522-12 (65 mg).

A solution of 522-12 in 4M HCl-dioxane (1 mL) was stirred at 0° C. for 1h. The volatiles were removed under reduced pressure. The residue waspurified by reverse phase chromatography (water:CH₃CN, 95:5 to 40:60) toafford 522 (14 mg). UPLC/MS(ES⁺): m/z 568.30 [M+H]⁺.

Example 273 Preparation of Compound 477

A mixture of 271-10 (50 mg, 0.1 mmol), 477-1 (16 mg, 0.1 mmol) and TEA(1 mmol) was dissolved in anhydrous DCM (4 mL) with stirring. Themixture was treated with HATU (38 mg, 0.1 mmol) in 1 portion. Afterstirring at r.t. for 30 mins, TFA (1 mL) was added. The solution wasstirred at r.t. for 2 h. The mixture was concentrated to dryness. Theresidue was purified by reverse prep-HPLC to afford 477 (28 mg, 48%) asa white solid. +ESI-MS: m/z 537.1 [M+H]⁺.

Example 274 Preparation of Compound 478

Compound 478 was prepared following the general procedure for preparing477 by using 2-chlorooxazole-4-carboxylic acid and 271-10. Crude 478 waspurified by prep-HPLC and obtained as a white solid (20 mg, 36%).+ESI-MS: m/z 520.9 [M+H]⁺.

Example 275 Preparation of Compound 485

To a solution of 485-1 (6 g, 15.4 mmol) in anhydrous DMF (95 mL) wasadded NaH (640 mg, 16 mmol, 60% in mineral oil) in small portions atr.t. After stirring for 10 mins, a solution of MeI (2.3 g, 16 mmol) inDMF (5 mL) was added dropwise, and the reaction was stirred for 1 h.After complete conversion of 485-1, the mixture was quenched with water,and extracted with EtOAc (150 mL×2). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by chromatography using (PE:EtOAc: 100:0 to 80:20) toafford 485-2 (5.8 g, 93.5%).

Compound 485 (white solid, 27 mg) was prepared following the generalprocedure for preparing 272 using 485-2 and(S)-3-methoxy-4-((2-oxopyrrolidin-3-yl)oxy)benzoic acid. +ESI-MS: m/z639.1 [M+H]⁺.

Example 276 Preparation of Compound 486

Compound 486 (white solid, 34 mg) was prepared following the generalprocedure for preparing 485 by using 486-1 and 271-10. +ESI-MS: m/z614.1 [M+H]⁺.

Example 277 Preparation of Compound 487

Compound 487 (white solid, 27.5 mg) was prepared following the generalprocedure for preparing 485 by using 487-1 and 271-10. +ESI-MS: m/z613.1 [M+H]⁺.

Example 278 Preparation of Compound 488

Compound 488 (white solid, 26 mg) was prepared following the generalprocedure for preparing 485 by using 488-1 and 271-10. +ESI-MS: m/z591.1 [M+H]⁺.

Example 279 Preparation of Compound 489

Compound 489 (white solid, 23 mg) was prepared following the generalprocedure for preparing 485 by using 489-1 and 271-10. +ESI-MS: m/z586.0 [M+H]⁺.

Example 280 Preparation of Compound 490

Compound 490 (white solid, 41 mg) was prepared following the generalprocedure for preparing 485 by using 490-1 and 271-10. +ESI-MS: m/z656.0 [M+H]⁺.

Example 281 Preparation of Compound 491

Compound 491 (white solid, 25 mg, 44%) was prepared following thegeneral procedure for preparing 485 by using 491-1 and 491-2. +ESI-MS:m/z 600.1 [M+H]⁺.

Example 282 Preparation of Compounds 495 and 496

To a solution of 495-1 (850 mg, 1.73 mmol) in MeOH (50 mL) was addedPd/C (210 mg, 5%) under N2 at r.t. The suspension was purged withhydrogen for several times. The mixture was stirred under hydrogen (15psi) at r.t. for 12 h. After complete conversion of 495-1, the mixturewas filtered through a pad of Celite, and the filtrate was concentratedto dryness. The residue was 495-2 (750 mg, 94.6%), which was useddirectly without further purification. +ESI-MS: m/z 458.2 [M+H]⁺.

A mixture of 495-2 (750 mg, 1.64 mmol), carboxyl acid 3 (340 mg, 1.64mmol) and TEA (1 mmol) is dissolved in anhydrous DMF (10 mL) withstirring. The solution was treated with HATU (623 mg, 1.64 mmol) in oneportion. After stirring at r.t. for 1˜2 h, the mixture was poured intocold water and extracted with EA (20 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography using PE:EA=1:1 as the eluent to give 495-3 as an oil(910 mg, 86%). +ESI-MS: m/z 648.1 [M+H]⁺.

To a stirring solution of 495-3 (910 mg, 1.41 mmol) in DCM (10 mL) wasadded TFA (5 mL) dropwise at r.t. The reaction was stirred for 30 minsand concentrated to dryness under reduced pressure. The residue wasneutralized by sat. sodium carbonate solution and extracted with EA (15mL×2). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by prep-HPLC and separated by SFC to give 495 (93 mg) and496 (82 mg) as a white solid. 495: +ESI-MS: m/z 548.1 [M+H]⁺; and 496:+ESI-MS: m/z 548.1 [M+H]⁺.

Example 283 Preparation of Compound 497

To a stirring solution of 314 (116 mg, 0.2 mmol),2-((tert-butoxycarbonyl)amino)acetic acid (35 mg, 0.20 mmol) and DIPEA(90 mg, 0.7 mmol) in anhydrous DCM (5 mL) was added HATU (76 mg, 0.2mmol) in one portion at 25° C. The solution was stirred for 1 h. Themixture was diluted with water and DCM. The organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give crude 497-1 (110 mg), which used directly withoutpurification. +ESI-MS: m/z 739.1 [M+H]⁺.

To a stirring solution of crude 497-1 (110 mg) in EA (10 mL) was addedHCl:EA (4 M, 5 mL) at r.t. The reaction was stirred for 30 mins with TLCmonitoring. After conversion of 497-1, the reaction was quenched withsat. sodium bicarbonate solution, and extracted with EA (10 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated to dryness. The residue was purified byprep-HPLC to give 497 (50 mg, 52.6%) as a white solid. +ESI-MS: m/z639.2 [M+H]⁺.

Example 284 Preparation of Compound 500

To a solution of 314 (58 mg, 0.1 mmol) and K₂CO₃ (27 mg, 0.2 mmol) inDMF (1 mL) was added methyl 2-bromoacetate (23 mg, 0.15 mmol) at r.t.The mixture was heated to 60° C. and stirred for 2 h. The reaction wascooled to r.t. and diluted with H₂O and EA. The combined organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-HPLC to give 500 as a white solid (30 mg,46.2%). +ESI-MS: m/z 654.1 [M+H]⁺.

Example 285 Preparation of Compound 501

To a solution of 500 (90 mg, 0.14 mmol) in MeOH (10 mL) was addedNH₃:MeOH (7M, 10 mL). The vial was sealed and heated to 60° C. for 2 h.The reaction was cooled to r.t. and diluted with H₂O (20 mL) and EA (20mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated to dryness. The residue was purifiedby prep-HPLC to give 501 as a white solid (49 mg, 54.7%). +ESI-MS: m/z639.1 [M+H]⁺.

Example 286 Preparation of Compound 502

To a solution of 500 (65 mg, 0.1 mmol) in co-solvent of THF (2 mL) andMeOH (2 mL) was added LiBH₄ (10 mg, 0.5 mmol) at r.t. The mixture wasstirred at r.t. for 30 mins. The reaction was quenched with H₂O andextracted with EA (10 mL×2). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to dryness atlow pressure. The residue was purified by prep-HPLC to give 502 as awhite solid (40 mg, 64.5%). +ESI-MS: m/z 626.0 [M+H]⁺.

Example 287 Preparation of Compound 503

To a solution of 503-1 (1.0 g, 2.5 mmol) in toluene (8 mL) was addedpyridine (590 mg, 7.5 mmol) at 0° C. The mixture was stirred at 0° C.for 5 mins and SOCl₂ (820 mg, 7.0 mmol) was added dropwise. Afteraddition, the mixture was stirred at 0° C. for 30 mins. The reaction wasquenched with H₂O and extracted with EA (10 mL×3). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography using PE:EA=5:1 as the eluent to give 503-2 as a solid(0.8 g, 85.1%). +ESI-MS: m/z 377.1 [M+H]⁺.

To a solution of 503-2 (0.8 g, 2.1 mmol) in DMSO (6 mL) was addedammonia water (1 mL) at 0° C. The mixture was stirred at r.t. for 30mins. The mixture was diluted with H₂O and extracted with EA (10 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated to dryness. The residue was purified by columnchromatography using PE:EA=3:1 as the eluent to give 503-3 as a solid(650 mg, 78.7%). +ESI-MS: m/z 394.1 [M+H]⁺.

To a solution of 503-3 (650 mg, 1.7 mmol) in MeOH (10 mL) was addedRaney Ni (0.7 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ for several times. The reaction was stirred under H₂(balloon) at r.t. for 30 mins. The mixture was filtered through a pad ofCelite, and the filtrate was concentrated to give 503-4 (550 mg), whichwas used directly without purification.

To a solution of 503-4 (37 mg, 0.10 mmol),4-cyclopropoxy-3-methoxybenzoic acid (21 mg, 0.10 mmol) and DIPEA (39mg, 0.3 mmol) in anhydrous DCM (3 mL) was added HATU (39 mg, 0.10 mmol)in one portion at 25° C. The solution was stirred at this temperaturefor 1 h. The reaction was diluted with H₂O and extracted with DCM (10mL×2). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated to dryness at low pressure. Theresidue was purified by prep-HPLC to give 503 as a white solid (35 mg,63.6%). +ESI-MS: m/z 553.9 [M+H]⁺.

Example 288 Preparation of Compound 504

Compound 504 (white solid, 49 mg) was prepared following the generalprocedure for preparing 503 by using 503-1. +ESI-MS: m/z 581.2 [M+H]⁺.

Example 289 Preparation of Compound 505

Compound 505 (white solid, 9 mg) was prepared following the generalprocedure for preparing 500 by using 314 and 1-bromo-2-m ethoxy ethaneas starting material. +ESI-MS: m/z 640.1 [M+H]⁺.

Example 290 Preparation of Compound 508

To a solution of 314 (290 mg, 0.5 mmol) in THF (5 mL) was added2-chloroacetaldehyde (0.5 g, 40% in H₂O) at r.t. The mixture was stirredfor 30 mins and NaBH₃CN (160 mg, 2.5 mmol) was added. The mixture wasstirred at r.t. for 30 mins. The reaction was quenched with H₂O andextracted with EA (10 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by column chromatography using PE:EA=1:1 as theeluent to give 508-1 as a solid (210 mg, 65.4%).

To a solution of 508-1 (210 mg, 0.33 mmol) in DMSO (5 mL) was added NaN₃(60 mg, 0.92 mmol) at r.t. The mixture was stirred at 60° C. for 30mins. The mixture was cooled to r.t. and diluted with H₂O and EA (10mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated to give crude 508-2 (190 mg) as a paleyellow solid, which was used directly without purification. +ESI-MS: m/z651.1 [M+H]⁺.

To a solution of 508-2 (190 mg, 0.29 mmol) in MeOH (15 mL) was addedPd/C (0.2 g) under N2 at r.t. The suspension was degassed under vacuumand purged with EE for several times. The mixture was stirred under Ehballoon for 30 mins at r.t. The mixture was filtered through a pad ofCelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by prep-HPLC to give 508 as a white solid (101 mg,55.5%). +ESI-MS: m/z 625.0 [M+H]⁺.

Example 291 Preparation of Compound 515

To a solution of 500 (180 mg, 0.28 mmol) in MeOH (5 mL) was added asolution of NaOH (50 mg, 1.25 mmol) in H₂O (5 mL) at r.t. The mixturewas stirred at 60° C. for 1 h. MeOH was evaporated, and the aqueousphase was acidified to pH=1 by addition of 1 N HCl solution. Thesolution was extracted with EA (10 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated atlow pressure. The residue was purified by prep-HPLC to give 515 as awhite solid (80 mg, 45.0%). +ESI-MS: m/z 640.0 [M+H]⁺.

Example 292 Preparation of Compound 516

To a solution of 314 (100 mg, 0.17 mmol) in DCM (2 mL) was addedCCl₃CONCO (36 mg, 0.189 mmol) at 0° C. The solution was stirred for 20mins. The solution was diluted with DCM (10 mL) and H₂O (10 mL). Theorganic phase was separated and concentrated under reduced pressure togive crude 516-1 (78 mg, 60.0%), which was used directly withoutpurification.

To a solution of 516-1 (78 mg, crude) in MeOH (1 mL) was added sat.NaHCO₃ solution (1 mL) and stirred at r.t. for 1 h. The mixture wasextracted with EA (10 mL×3). The combined organic layers were washed bybrine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by prep-HPLC to give 516 (28 mg, 44.4%) as a whitesolid. +ESI-MS: m/z 625.1 [M+H]⁺.

Example 293 Preparation of Compound 517

Compound 517 (white solid, 87 mg, 35.3%) was prepared following thegeneral procedure for preparing 232 and 504 by using 517-1 and ethyl2,2-difluoroacetate. +ESI-MS: m/z 536.0 [M+H]⁺.

Example 294 Preparation of Compound 518

To a solution of 518-1 (3.56 g, 10.0 mmol) and CsF (3.0 g, 20.0 mmol) inMeCN (15 mL) was added 18-crown-6 (3.6 g, 13.6 mmol) at r.t. The mixturewas heated to 100° C. and stirred at 100° C. for 5 h. The mixture wascooled to r.t., and the solid was removed by filtration. The filtratewas concentrated and purified by column chromatography using PE:EA=5:1as the eluent to give 518-2 as a solid (2.01 g, 67.3%). +ESI-MS: m/z297.9 [M+H]⁺.

Compound 518 (white solid, 21 mg, 45.3%) was prepared following thegeneral procedure for preparing 503 by using 518-2. +ESI-MS: m/z 518.0[M+H]⁺.

Example 295 Preparation of Compound 525

To a solution of 525-1 (2.8 g, 10.0 mmol) and AIBN (168 mg, 1.0 mmol) inCCl₄ (20 mL) was added NBS (1.9 g, 10.7 mmol) at r.t. The mixture washeated to 70° C. and stirred for 3 h. The mixture was cooled to r.t. andconcentrated under reduced pressure. The residue was purified by columnchromatography using PE:EA=15:1 as the eluent to give 525-2 as a solid(2.5 g, 69.8%). +ESI-MS: m/z 359.9 [M+H]⁺.

To a solution of 525-2 (2.5 g, 7.0 mmol) in DMSO (15 mL) was added NaN₃(1.1 g, 16.9 mmol) at r.t. The reaction was heated to 60° C. and stirredfor 1 h. The reaction was cooled to r.t. The mixture was diluted withH₂O and extracted with EA (60 mL×3). The organic layers were dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by column chromatography using PE:EA=1:1 as the eluent togive 525-3 as a solid (1.8 g, 81.8%). +ESI-MS: m/z 322.8 [M+H]⁺.

To a solution of 525-3 (1.8 g, 5.6 mmol) in MeOH (15 mL) was added SnCl₂2H₂O (2.5 g, 11.1 mmol) at r.t. The mixture was stirred for 1 h with TLCmonitoring. After 525-3 was consumed, the reaction was quenched withsat. NaHCO₃ and extracted with EA (30 mL×2). The combined organicsolution was dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. Crude 525-4 (1.0 g) was used directly without furtherpurification.

To a solution of 525-4 (1.0 g, 3.4 mmol) in DCM (15 mL) was added BOC₂O(1.4 g, 6.4 mmol) at r.t. The mixture was stirred at r.t. for 3 h andthen concentrated to dryness. The residue was purified by chromatographyusing PE:EA=5:1 as the eluent to give 525-5 as a solid (0.8 g, 61.5%).

To a solution of 525-5 (0.8 g, 2.0 mmol) and CF₃COOEt (1.7 g, 11.9 mmol)in THF (10 mL) was added isopropylmagnesium chloride (4 mL, 2.0 M inTHF) dropwise at r.t. under N₂. The mixture was stirred at r.t. for 30mins. The reaction was quenched with aq. NH₄Cl and extracted with EA (20mL×3). The combined organic solution was dried over anhydrous Na₂SO₄,and concentrated under reduced pressure. Crude 525-6 (0.6 g) was useddirectly without purification.

Compound 525 (white solid, 130 mg) was prepared following the generalprocedure for preparing 272 using 525-6. +ESI-MS: m/z 582.1 [M+H]⁺.

Example 296 Preparation of Compound 526

To a solution of 526-1 (10 g, 0.05 mol) in anhydrous DCM (100 mL) wasadded oxalyl dichloride (12.7 g, 0.1 mmol) and several drops of DMF. Themixture was stirred for 1 h and evaporated under reduced pressure togive 526-2.

To a solution of 2-methylbut-3-yn-2-amine (4.4 g, 52.5 mmol) and Et₃N(10.1 g, 0.1 mmol) in anhydrous DCM (100 mL) was added a solution ofcrude 526-2 in DCM (50 mL) dropwise at r.t. The solution was stirred for1 h, washed with water and brine (50 mL), dried with anhydrous Na₂SO₄and concentrated to give 526-3. The residue was used directly withoutfurther purification.

526-3 (2.58 g, 10 mmol) in PhNO₂ (10 mL) was put in a microwave tube.The solution was heated to 210° C. by microwave irradiation and stirredfor 5 mins. The reaction was cooled to r.t. and concentrated at lowpressure. The residue was purified by column chromatography usingPE:EA=10:1˜1:1 to give 526-4 (610 mg, 31.1%). +ESI-MS: m/z 197.1 [M+H]⁺.

To a stirring solution of DMAE (1.068 g, 12 mmol) in THF (10 mL) wasadded n-BuLi (10 mL, 25 mmol) at −78° C. After 5 mins, a solution of526-4 (588 mg, 3 mmol) in anhydrous THF (3 mL) was added dropwise at−78° C. The mixture was stirred for 10 mins and a solution of I₂ (6.35g, 25 mmol) in THF was added dropwise at −78° C. After 20 mins, thereaction was quenched with sat. aq. Na₂SO₃. The solution was extractedwith EA (50 mL×2). The organic phase was washed with brine and driedover anhydrous Na₂SO₄. The organic phase was concentrated at lowpressure, and the residue was purified by column chromatography usingPE:EA=1:1 as the eluent to give 526-5 (650 mg, 51.0%). +ESI-MS: m/z322.9 [M+H]⁺.

To a solution of 526-5 (642 mg, 2 mmol) and CF₃COOEt (468 mg, 4 mmol) inanhydrous THF (5 mL) was added iPrMgCl (3 mL, 6 mmol) dropwise at r.t.The solution was stirred for 10 mins. The reaction was quenched withwater and extracted with EA (20 mL×2). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated todryness. The residue was purified by column chromatography usingPE:EA=1:1 as the eluent to give 526-6 (302 mg, 51.3%).

To a solution of 526-6 (300 mg, 1.03 mmol) in DME/H₂O (4 mL/1 mL),Cs₂CO₃ (502 mg, 1.55 mmol), (3-chloro-4-fluorophenyl)boronic acid (270mg, 1.87 mmol) and Pd(dppf)Cl₂ (50 mg, 65 mmol) were added at r.t. underN₂. The vial was sealed and heated to 100° C. for 40 mins by microwaveirradiation. After cooling to r.t., the mixture was diluted with EA (10mL) and brine (10 mL). The aqueous layer was extracted with EA (10mL×2). The combined organic layers were washed with brine (10 mL), driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA=1:1 as theeluent to give 526-7 (310 mg, 73.7%). +ESI-MS: m/z 386.9 [M+H]⁺.

To a solution of 526-7 (310 mg, 0.76 mmol) in dry THF (5 mL) was addedBH₃.Me₂S (1 mL, 10 mmol) at r.t. The solution was stirred in apre-heated 80° C. oil bath for 2 h. The solution was cooled to r.t., andthe reaction was quenched with H₂O. The mixture was extracted with EA(20 mL×2). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography using EA as the eluent to give526-8 (140 mg, 49.2%) as a gray solid.

To a solution of 526-8 (140 mg, 0.37 mmol) in toluene (3 mL) was addedEt₃N (75 mg, 0.74 mmol) and Boc₂O (87 mg, 0.44 mmol) at r.t. Thesolution was stirred in a pre-heated 100° C. oil bath for 3 h. Thesolution was cooled to r.t. and diluted with EA (20 mL) and water (20mL). The organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography using PE:EA=5:1 as the eluent to give 526-9 (90mg, 51.0%). +ESI-MS: m/z 474.9 [M+H]⁺.

To a stirred solution of 526-9 (90 mg, 0.189 mmol) in DMSO (2 mL) wasadded IBX (212 mg, 0.75 mmol) in one portion, and stirred at 40° C. for2 h. The solution was poured into aq. NaHCO₃ and extracted with EA (10mL×2). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography using 0-30% EA in PE as the eluentto give 526-10 (60 mg, 66.7%).

Compound 526 (white solid, 4 mg, 13.7%) was prepared following thegeneral procedure for preparing 272 using 526-10. +ESI-MS: m/z 594.1[M+H]⁺.

Example 297 Preparation of Compound 528

To a stirred solution of 528-1 (50 g, 310 mmol) in anhydrous THF (1.2 L)was added LDA (310 mL, 620 mmol) at −78° C. slowly under N₂, and themixture stirred at −78° C. for 0.5 h. A solution of dimethyl carbonate(67.1 g, 750 mmol) in dry THF (150 mL) was added dropwise. The solutionwas allowed to warm to 0° C. and stirred for 1 h below 0° C. Thereaction was quenched with aq. NH₄Cl (500 mL), and extracted with EA(500 mL×3). The combined organic phase was washed with aqueous sodiumbicarbonate, brine, and dried over anhydrous sodium sulfate. The organiclayer was concentrated to dryness, and the residue was purified bycolumn chromatography (PE:EA=20:1) to give 528-2 (50 g, 73.5%) as acolorless oil.

To a solution of crude 528-2 (50 g, 230 mmol) in dioxane:H₂O (6:1) (1 L)was added (3-chloro-4-fluorophenyl) boronic acid (40 g, 230 mmol),Cs₂CO₃ (223.3 g, 680 mmol) and Pd(dppf)Cl₂ (16.8 g, 23 mmol) under N2.The mixture was degassed for 3 times and refilled with N2. The reactionwas stirred at 80° C. in a pre-heated oil bath for 4 h. After cooling tor.t., the mixture was diluted with water (1.5 L) and extracted with EA(1 L×3). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by column chromatography (PE:EA=20:1˜15:1) to yield528-3 (42 g, 58.7%) as a light yellow solid.

To a solution of 528-3 (9.39 g, 30.00 mmol) in HOAc (100 mL) was addedBr₂ (5.28 g, 33 mmol) dropwise at r.t. The mixture was heated at 60° C.for 5 h. The reaction was cooled to r.t. and concentrated under reducedpressure to dryness. The residue was used directly without furtherpurification. +ESI-MS: m/z 393.7 [M+H]⁺.

To a solution of crude 528-4 (10.0 g) in MeOH (100 mL) was added NaN₃(3.3 g, 50.8 mmol) at 25° C., and the mixture was stirred at 25° C. for1 h. The mixture was diluted with H₂O (150 mL), and extracted with andEA (150 mL×3). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA =20:1˜5:1 asthe eluent to give 528-5 (8.02 g, 88%).

To a solution of 528-5 (8.02 g, 22.6 mmol) and Boc₂O (14.8 g, 67.77mmol) in MeOH (100 mL) was added Pd/C (3.0 g, 10%) under N2. Thesuspension was degassed and purged with H2 for several times. Themixture was stirred under H2 balloon at 25° C. for 3 h. TLC showed thatthe starting material was consumed completely. The mixture was filteredthrough a pad of Celite, and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography usingPE:EA=50:1˜5:1) to give 528-6 (5.5 g). +ESI-MS: m/z 428.9 [M+H]⁺.

528-13 (white solid, 80 mg) was prepared following the general procedurefor preparing 272 using 528-6. +ESI-MS: m/z 712.1 [M+H]⁺.

To a solution of 528-13 (80.00 mg crude) in a co-solvent of MeOH (5 mL)and THF (5 mL) was added NaBH₄ (40 mg, 1.05 mmol), and the mixture wasstirred at 25° C. for 2 h. The reaction was quenched by H₂O andextracted by EA (10 mL×3). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by prep-TLC to give 528-14 (51 mg). +ESI-MS: m/z684.1 [M+H]⁺.

Compound 528 (white solid, 18 mg, 39.9%) was prepared following thegeneral procedure for preparing 272 using 528-14. +ESI-MS: m/z 584.0[M+H]⁺.

Example 298 Preparation of Compound 529

To a solution of 529-1 (150.00 mg) in MeOH (50 mL) was added Ra—Ni (0.15g) under N₂. The suspension was degassed and purged with H₂ for severaltimes. The mixture was stirred under Eh balloon at 25° C. for 2H. TLC(PE:EA=1:1) showed that the starting material was consumed. The mixturewas filtered, and the filtrate was concentrated to give 529-2 (90 mg,crude), which was used directly without further purification.

Compound 529 (white solid, 13 mg) was prepared following the generalprocedure for preparing 528 by using 529-2. +ESI-MS: m/z 550.1 [M+H]⁺.

Example 299 Preparation of Compound 532

Compound 532 (white solid, 13 mg) was prepared following the generalprocedure for preparing 501 and 272 by using 532-1. +ESI-MS: m/z 597.1[M+H]⁺.

Example 300 Preparation of Compound 533

To a solution of 533-1 (10 g, 31.9 mmol) in anhydrous THF (100 mL) wasadded LiHMDS (63.9 mL, 63.9 mmol) dropwise, and stirred at −78° C. for30 mins. A solution of MeI (9.07 g, 63.9 mmol) in dry THF (50 mL) wasadded dropwise. The mixture was warmed to 0° C. and stirred at 0° C. for1 h. The reaction was quenched with water (100 mL) and extracted with EA(150 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and concentrated in vacuum to dryness.The residue was purified by column chromatography (PE:EA=10:1) to yield533-2 (3.5 g, 32%) as a light yellow solid.

533-4 (crude, yellow oil) was prepared following the general procedurefor preparing 501 by using 2. +ESI-MS: m/z 369.0 [M+H]⁺.

To a solution of 533-4 (500.00 mg, 1.35 mmol) in MeOH (30 mL) was addedSnCl₂.2H₂O (760.40 mg, 3.39 mmol) in one portion at r.t. under N₂, andthe mixture was stirred for 2 h. TLC showed that the reaction wascompleted. The mixture was diluted with water (20 mL). The solution wasextracted with EA (30 mL×3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue was used in the next step without purification.

To a solution of 533-5 (0.5 g, 1.46 mmol) and CbzCl (745.56 mg, 4.37mmol) in DCM (15 mL) was added NaHCO₃ (489.61 mg, 5.83 mmol) in oneportion, and the mixture was stirred at r.t. for 1 h. The solution waspoured into ice-water (15 mL) and stirred for 20 mins. The aqueous phasewas extracted with EA (40 mL×3). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(PE:EA=30:1˜10:1) to afford 533-6 (0.4 g) as a yellow solid. +ESI-MS:m/z 477.1 [M+H]⁺.

To a solution of 533-6 (0.4 g, 0.84 mol) in THF (40 mL) was added LiBH₄(55 mg, 2.5 mmol) in one portion, and the mixture stirred at r.t. for 1h. TLC showed that the reaction was completed. The mixture was pouredinto ice-water (15 mL) and stirred for 20 mins. The aqueous phase wasextracted with EA (40 mL×3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated at lowpressure. The residue was purified by column chromatography(PE:EA=30:1˜2:1) to afford 533-7 (320.00 mg, 85%) as a yellow solid.+ESI-MS: m/z 448.6 [M+H]⁺.

To a solution of 533-7 (320 mg, 0.71 mmol) in DME (5 mL) and H₂O (1 mL)were added4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (320mg, 1.42 mmol), Cs₂CO₃ (0.7 g, 2.13 mmol), and Pd(dppf)Cl₂ (52 mg, 0.07mol) under N2. The reaction flask was sealed and stirred at 110° C. bymicrowave irradiation for 1 h. The reaction was cooled to r.t., anddiluted with EA and water. The organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using 3-20% of EA in PE asthe eluent to give 533-8 (220 mg, 60%). +ESI-MS: m/z 508.9 [M+H]⁺.

To a mixture of 533-8 (100.00 mg, 0.2 mmol) in t-BuOH (1.5 mL) and H₂O(0.5 mL), were added K₂OsO₄H₂O (11 mg, 0.06 mmol) and BocHN-OTs (113 mg,0.39 mmol), and the mixture was stirred at r.t. overnight. The mixturewas poured into ice-water, stirred for 20 mins and extracted with EA (10mL×3). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA=30:1˜20:1 asthe eluent to give 533-9 (50 mg, 40%) as a yellow solid. +ESI-MS: m/z642.1 [M+H]⁺.

To a solution of 533-9 (50.00 mg, 0.078 mmol) in DCM (2 mL) was addedTFA (1 mL). The mixture was stirred at r.t. for 1 h. The solution waspoured into ice-water (5 mL) and neutralized with sat. NaHCO₃ solution.The aqueous phase was extracted with EA (5 mL×3). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using EA as the eluent to give 533-10 (30.00 mg, 71%) asa yellow solid. +ESI-MS: m/z 542.1 [M+H]⁺.

533-11 (yellow solid, 30 mg, 74%) was prepared following the generalprocedure for preparing 272 using 533-11. +ESI-MS: m/z 732.3 [M+H]⁺.

To a solution of 533-11 (30 mg) in CH₃CN (1 mL) was added one drop ofTMSI at r.t. The mixture was stirred at r.t. for 10 mins. The mixturewas poured into water, neutralized with sat. NaHCO₃ solution andextracted with EA (10 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC to give 533(23.00 mg) as a white solid. +ESI-MS: m/z 597.9 [M+H]⁺.

Example 301 Preparation of Compound 534

To a solution of 534-1 (6 g, 18.3 mmol) and TEA (18.5 g, 183 mmol) inTHF (60 mL) was added aq. HCHO (15 g, 183 mmol) at 25° C. under N₂. Themixture was stirred at 25° C. for 2 h. TLC (PE:EA=5:1) showed that thereaction was completed. The mixture was diluted with water and extractedwith EA (100 mL×3). The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography usingPE:EA=30:1˜5:1 as the eluent to afford 534-2 (5.1 g, 77%) as a whiteoil. +ESI-MS: m/z 358.1 [M+H]⁺.

To a solution of 534-2 (1.76 g, 4.91 mmol) in DCM (20 mL) was added DAST(7.91 g, 49.10 mmol) dropwise at −78° C. under N₂. The mixture wasslowly warmed to 25° C., and stirred for 12 h. TLC (PE:EA=5:1) showedthat the reaction was completed. The mixture was cooled to 0° C. andquenched with sat. NaHCO₃ solution. The aqueous phase was extracted withEA (20 mL×3). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated at low pressure. Theresidue was purified by column chromatography using PE:EA=100:1˜ 60:1 asthe eluent to afford 534-3 (0.6 g, 34%) as a white oil. +ESI-MS: m/z360.1 [M+H]⁺.

To a solution of 534-3 (590 mg, 1.64 mmol) in MeOH (6 mL) was added asolution of NaOH (260 mg, 6.6 mmol) in H₂O (6 mL) at r.t. The mixturewas heated to 60° C. and stirred for 2 h. The mixture was cooled tor.t., and the organic solvent was removed under reduced pressure. The pHof aqueous phase was adjusted to ˜3 using 2M HCl and extracted with EA(30 mL×3). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to give 534-4(503 mg, 88%) as a white solid.

To a solution of 534-4 (438 mg, 1.27 mmol), DIPEA (655 mg, 5.07 mmol)and BnOH (274 mg, 2.53 mmol) in toluene (5 mL) was added DPPA (698 mg,2.54 mmol) at r.t. under N2. The mixture was heated to 80° C. andstirred for 12 h. The mixture was cooled to r.t. and concentrated underreduced pressure. The residue was purified by column chromatographyusing PE:EA=30:1˜5:1 as the eluent to afford 534-5 (450.00 mg, 78.52%)as a white solid.

Compound 534 (white solid, 21 mg, 45.9%) was prepared following thegeneral procedure for preparing 533 using 534-5. +ESI-MS: m/z 600.0[M+H]⁺.

Example 302 Preparation of Compound 535

To a solution of 535-1 (2.0 g, 4.2 mmol) in MeOH (20 mL) was added NaBH₄(476 mg, 12.6 mmol) at r.t. in small portions. The solution was stirredfor 30 mins and quenched with H₂O. The mixture was extracted with EA (50mL). The organic phase was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bycolumn chromatography using PE:EA=1:1 to give 535-2 (1.6 g, 85%) as awhite solid. +ESI-MS: m/z 449.1 [M+H]⁺.

To a solution of 535-2 (1.40 g, 3.1 mmol) in THF (20 mL) were added Ag₂O(723 mg, 3.1 mmol) and MeI (1.77 g, 12.5 mmol) at r.t. The mixture wassealed and heated to 40° C. The reaction was stirred overnight andconcentrated to dryness at low pressure. The residue was purified bycolumn chromatography using PE:EA=10:1 as the eluent to give 535-3 (450mg, 31%). +ESI-MS: m/z 463.1 [M+H]⁺.

Compound 535 (white solid, 11 mg, 22%) was prepared following thegeneral procedure for preparing 533 using 535-3. +ESI-MS: m/z 612.1[M+H]⁺.

Example 303 Preparation of Compound 536

Compound 536 (white solid, 65 mg, 83%) was prepared following thegeneral procedure for preparing 533 and 501 using 536-1. +ESI-MS: m/z611.2 [M+H]⁺.

Example 304 Preparation of Compound 537

To a solution of 537-1 (0.7 g, 2.1 mmol) in THF (8 mL) was added LiHMDS(3.2 mL 1 M in THF) at −78° C. in a period of 1 minute under N₂. Afterstirring at −78° C. for 10 minutes, a solution of MOMCl (340 mg, 4.2mmol) in THF (2 mL) was added at −78° C. in a period of 1 min under N₂.The reaction mixture was warmed to room temperature and stirred for 20minutes. LCMS showed that 537-1 was consumed completely. The reactionwas quenched by water and extracted with EA (20 mL×3). The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give 537-2 (720 mg,82%) as colorless oil. +ESI-MS: m/z 372.1 [M+H]⁺.

537-8 (white solid, 45 mg, 78%) was prepared following the generalprocedure for preparing 533 using 537-2. +ESI-MS: m/z 746.1 [M+H]⁺.

To a solution of 537-8 (45 mg, 0.06 mmol) in TFA (1 mL) was addedHBr/HOAc (1 mL, 40%) at r.t. The reaction mixture was stirred at roomtemperature until all starting material was consumed (followed by LCMS).The resulting mixture was concentrated under reduced pressure. Theresidue was neutralized with aqueous NaHCO₃ and extracted with EA. Thecombined organic phase was concentrated under reduced pressure. Theresidue was purified by Pre-HPLC to afford 537 (9 mg, 16.3%) as a whitesolid. +ESI-MS: m/z 654.1 [M+H]⁺.

Example 305 Preparation of Compound 540

Compound 540 (white solid, 175 mg, 71%) was prepared following thegeneral procedure for preparing 534 using 540-1. +ESI-MS: m/z 604.1[M+H]⁺.

Example 306 Preparation of Compound 541

Compound 541 (white solid, 13 mg, 18.4%) was prepared following thegeneral procedure for preparing 537 and 528 using 541-1. +ESI-MS: m/z616.0 [M+H]⁺.

Example 307 Preparation of Compound 544

To a solution of CH₃CN (24.6 g, 600 mmol) in toluene (200 mL) was addedn-BuLi (120 mL, 2.5 M in hexane) dropwise at −78° C. under N₂. Themixture was stirred at −78° C. for 30 mins. The mixture was treated witha solution of 544-1 (36.0 g, 120 mmol) in toluene (200 mL). The mixturewas warmed to r.t. and stirred for 2 h. The reaction was quenched withsat. aq. NH₄Cl, and extracted with EA (4×200 mL). The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by columnchromatography to give 544-2 as a white solid (31.5 g, 85.0%). +ESI-MS:m/z 308.9 [M+H]⁺.

To a solution of 544-2 (30.9 g, 100 mmol) in MeOH (600 mL) was addedNaBH₄ (19 g, 500 mmol) in portions at 0° C., and stirred at 0° C. for 4h. The mixture was quenched with water, and extracted with EA (4×300mL). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was further purified by column chromatography to afford 544-3 asa light yellow solid (28.0 g, 90.0%). +ESI-MS: m/z 310.9 [M+H]⁺.

To a solution of 544-3 (5 g, 16.08 mmol) in MeOH (100 mL) was addedSOCl₂ (20 mL) at 0° C. dropwise. The mixture was heated to reflux andstirred for 48 h. The mixture was cooled to r.t. The solution wasneutralized with sat. aq. NaHCO₃, and extracted with EA (4×300 mL). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography to afford 544-4 as a light yellowsolid (3.32 g, 60.0%).

Compound 544-5 (light yellow solid, 2.65 g, 90%) was prepared wasprepared following the general procedure for preparing 544-3 using544-4. +ESI-MS: m/z 315.7 [M+H]⁺.

To a solution of 544-5 (2.65 g, 8.38 mmol) and TEA (2.54 g, 25.15 mmol)in DCM (20 mL) was added MsCl (2.88 g, 25.15 mmol) at 0° C. The mixturewas stirred at r.t. for 2 h. The reaction was quenched with sat. aq.NaHCO₃ and extracted with EA (4×100 mL). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated at low pressure. The residue was purified by columnchromatography to afford 544-6 as a light yellow solid (3.2 g, 80.8%).

To a solution of 544-6 (3.2 g, 8.4 mmol) in toluene (50 mL) were addedBnNH₂ (5.4 g, 50.3 mmol), K₂CO₃ (6.9 g, 50.3 mmol), and KI (100 mg) atr.t. The mixture was stirred at 160° C. for 6 h. The mixture was cooledto r.t. and diluted with water. The solution was extracted with EA(4×100 mL). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated at low pressure. The residuewas purified by column chromatography to afford 544-7 as a light yellowsolid (1.1 g, 33.9%). +ESI-MS: m/z 386.9 [M+H]⁺.

Compound 544 (white solid, 450 mg, 40.3%) was prepared was preparedfollowing the general procedure for preparing 528 using 544-7. +ESI-MS:m/z 670.3 [M+H]⁺.

Example 308 Preparation of Compounds 545 and 546

Compounds 545 (white solid, 112 mg) and 546 (white solid, 107 mg) wasprepared following the general procedure for preparing 495 and 496 using545-1 and 545-2. 545: +ESI-MS: m/z 566.2 [M+H]⁺; and 546: +ESI-MS: m/z566.2 [M+H]⁺.

Example 309 Preparation of Compounds 547 and 548

Compounds 547 (white solid, 45 mg) and 548 (white solid, 48 mg) wasprepared following the general procedure for preparing 271 and 272 using547-1 and 547-2. 547: +ESI-MS: m/z 599.1 [M+H]⁺; and 548: +ESI-MS: m/z599.1 [M+H]⁺.

Example 310 Preparation of Compounds 549 and 550

Compounds 549 (white solid, 102 mg) and 550 (white solid, 108 mg) wasprepared following the general procedure for preparing 271 and 272 using549-1 and 549-2. 549: +ESI-MS: m/z 585.9 [M+H]⁺; and 550: +ESI-MS: m/z586.0 [M+H]⁺.

Example 311 Preparation of Compounds 551 and 552

Compounds 551 (white solid, 78 mg) and 552 (white solid, 72 mg) wasprepared following the general procedure for preparing 271 and 272 using551-1 and 551-2. 551: +ESI-MS: m/z 600.2 [M+H]⁺; and 552: +ESI-MS: m/z600.2 [M+H]⁺.

Example 312 Preparation of Compounds 553 and 554

Compounds 553 (white solid, 35 mg) and 554 (white solid, 45 mg) wasprepared following the general procedure for preparing 495 and 496 using553-1 and 553-2. 553: +ESI-MS: m/z 552.2 [M+H]⁺; and 554: +ESI-MS: m/z552.1 [M+H]⁺.

Example 313 Preparation of Compound 555

To a solution of 555-1 (2.74 g, 10 mmol) in anhydrous THF (30 mL) wasadded n-BuLi (4.8 mL, 2.5 M in hexane) dropwise at −78° C. under N₂. Themixture was stirred at −78° C. for 20 mins, and then treated with asolution of tert-butyl 3-oxoazetidine-1-carboxylate (1.71 g, 10.00 mmol)in anhydrous THF (5 mL) at −78° C. The solution was stirred for 30 minsat −78° C. The reaction was quenched with water and extracted with EA(3×50 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA=9:1 as theeluent to afford 555-2 (1.05 g, 33%). +ESI-MS: m/z 319.1 [M+H]⁺.

To a solution of 555-2 (0.8 g, 2.52 mmol) and (3-chloro-4-fluorophenyl)boronic acid (440 mg, 2.52 mmol) in dioxane:H₂O (10:1 mL) were addedCs₂CO₃ (1.23 g, 3.78 mmol) and Pd(dppf)Cl₂ (185.00 mg, 0.25 mmol) underN₂. The mixture was heated to 80° C. in an oil bath and stirred for 1 h.The mixture was cooled to r.t., poured into H₂O (20 mL) and extractedwith EA (3×30 mL). The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA=9:1 as theeluent to afford 555-3 (780 mg). +ESI-MS: m/z 413.1 [M+H]⁺.

To a solution of 555-3 (780 mg, 1.89 mmol) in DCM (8 mL) was added TFA(2 mL), and the mixture stirred at r.t. for 30 mins. The mixture wasconcentrated under reduced pressure, and the residue was dissolved inDCM (10 mL) and Et₃N (572 mg, 5.65 mmol). CbzCl (643 mg, 3.77 mmol) wasadded slowly at r.t., and the mixture was stirred for 2 h. The solutionwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduce pressure. The residue was purified by column chromatographyusing PE:EA=4:1 as the eluent to give 555-5 (720.00 mg). +ESI-MS: m/z447.1 [M+H]⁺.

Compound 555 (white solid, 3.5 mg, 16.3%) was prepared following thegeneral procedure for preparing 533 using 555-5. +ESI-MS: m/z595.9[M+H]⁺.

Example 314 Preparation of Compounds 561 and 562

Compounds 561 (white solid, 50 mg) and 562 (white solid, 48 mg) wasprepared following the general procedure for preparing 495 and 496 using561-1 and 561-2. 561: +ESI-MS: m/z 565.1 [M+H]⁺; and 562: +ESI-MS: m/z565.1 [M+H]⁺.

Example 315 Preparation of Compound 563

A solution of 563-1 (3.00 g, 10.56 mmol) and tetraethoxytitanium (7.23g, 31.68 mmol) in anhydrous THF (60 mL) was stirred for 5 mins. Thesolution was treated with 2-methylpropane-2-sulfamide (1.92 g, 15.84mmol) and stirred at 70° C. for 5 h. The mixture was cooled to r.t., andthe reaction was quenched with sat. aq. NaHCO₃ until white titaniumsalts precipitate was formed. The suspension was filtered through a padof Celite, and the cake was washed with EA. The aqueous was extractedwith EA. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography to give 563-2 (3.50 g,85.6%). +ESI-MS: m/z 387.0 [M+H]⁺.

To a solution of 563-2 (3.50 g, 9.0 mmol) in anhydrous THF (15 mL) wasadded allylmagnesium bromide (13.6 mL, 1.0 M in THF) at −78° C. underN₂, and the mixture was stirred at −78° C. for 1 h. The mixture wasallowed to warm to 25° C. and stirred for another 1 h. The reaction wasquenched with aq. NH₄Cl solution and extracted with EA (3×30 mL). Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified column chromatography to afford 563-3 (1.20 g, 31%) as ayellow solid. +ESI-MS: m/z 429.1 [M+H]⁺.

Ozone was bubbled into a solution of 563-3 (1.2 g, 2.8 mmol) inanhydrous MeOH (30 mL) at −78° C. for 10 mins. After excess O3 waspurged by nitrogen, NaBH₄ (420 mg 11.2 mmol) was added at 25° C. inportions. The solution was stirred for 30 mins at r.t. The reaction wasquenched with H₂O and extracted with EA (3×60 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography using PE:EA=2:1 as the eluent to give 563-4 (1.02 g, 83%)as a solid. +ESI-MS: m/z 433.1 [M+H]⁺.

To a solution of 563-4 (1.01 g, 2.5 mmol) and PPh₃ (1.0 g, 3.8 mmol) inanhydrous THF (20 mL) was added DIAD (870 mg, 4.3 mmol) dropwise at 25°C. under N₂. The mixture was heated to 70° C. and stirred for 4 h. Themixture was cooled to 25° C. and concentrated under reduced pressure.The residue was purified by column chromatography to afford 563-5 (902mg, 85%) as a solid.

To a solution of 563-5 (902 mg 2.2 mmol) in dioxane (8 mL) was addedcone. HCl (1 mL, 12 M) in one portion, and stirred at 25° C. for 1 h.The mixture was concentrated to give 563-6 (750 mg), which was used forthe next step without further purification.

563-6 (750 mg) and NaHCO₃ (607 mg, 7.2 mmol) were dissolved in DCM (10mL) and H₂O (1 mL). The solution was treated with CbzCl (617 mg 3.6mmol) at r.t. The mixture was stirred at r.t. for 1 h. The mixture wasdiluted with water and extracted with EA (3×30 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford 563-7 (990 mg, 93%). +ESI-MS: m/z 444.9 [M+H]⁺.

563-8 (white solid, 1.1 g, 16.3%) was prepared following the generalprocedure for preparing 533 using 563-7. +ESI-MS: m/z 595.9 [M+H]⁺.563-9 (402 mg) was obtained by SFC separation of 563-8 (1.1 g).

Compound 563 (white solid, 20 mg, 33%) was prepared following thegeneral procedure for preparing 533 using 563-9. +ESI-MS: m/z 593.9[M+H]⁺.

Example 316 Preparation of Compound 564

564-3 was prepared as described in Franck, D. et al., Bioorganic &Medicinal Chemistry (2013) 21(3):643-652.

To a solution of 564-4 (11.22 g, 35.7 mmol) in anhydrous THF (200 mL)was added LiHMDS (286 mL 1 M in THF) in portions at −78° C. under N₂.The mixture was stirred at −78° C. for 30 mins. The mixture was treatedwith a solution of 564-3 (22 g, 71.4 mmol) in anhydrous THF (50 mL)dropwise. The mixture was warmed to r.t. and stirred for 3 h. Thereaction was quenched with ice-water (150 mL). The aqueous phase wasextracted with EA (3×200 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography usingPE:EA=30:1˜10:1 as the eluent to afford 564-5 (11.0 g, 70% purity) as alight yellow oil. +ESI-MS: m/z 460.0 [M+H]⁺.

To a solution of 564-5 (11.0 g, 23.9 mmol) in anhydrous THF (60 mL) wasadded LiAlH₄ (907 mg, 23.9 mmol) in portions at 0° C. under N₂. Themixture was stirred at 0° C. for 30 mins. The reaction was quenched byice-water and filtered via a pad of Celite. The filtrate was extractedwith EA (3×100 mL). The combined organic phase was washed with brine,dried with anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using PE:EA=30:1˜20:1 asthe eluent to afford 564-6 (3.8 g, 28% yield, 81% purity) as a lightyellow oil. +ESI-MS: m/z 432.1 [M+H]⁺.

To a solution of 564-6 (0.8 g, 2.34 mmol) and TEA (0.71 g, 7.01 mmol) inDCM (10 mL) was added MSCl (270 mg, 2.34 mmol) dropwise at 0° C., andthe mixture was stirred at 20° C. for 30 mins. The mixture was pouredinto ice-water (50 mL) and extracted with EA (3×20 mL). The combinedorganic phase was washed with brine, dried with anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford 564-7 (0.6 g,crude) as a yellow oil, which was used for next step directly. +ESI-MS:m/z 509.9 [M+H]⁺.

To a solution of crude 564-7 (0.6 g, 1.43 mmol) in DMSO (6 mL) was addedNaBH₄ (270 mg, 7.14 mmol) in one portion at r.t. under N₂. The mixturewas stirred at 50-60° C. for 12 h. The reaction was cooled to r.t.,quenched with ice-water and extracted with EA (3×20 mL). The combinedorganic phase was washed with brine, dried with anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography using PE:EA=30:1˜8:1 as the eluent toafford 564-8 (0.3 g, 78% purity) as a yellow solid. +ESI-MS: m/z 415.9[M+H]⁺.

Compound 564 (white solid, 2.7 mg) was prepared following the generalprocedure for preparing 533 using 564-8. +ESI-MS: m/z 609.1 [M+H]⁺.

Example 317 Preparation of Compound 569

Compound 569 (white solid, 53 mg, 74%) was prepared following thegeneral procedure for preparing 495 using 569-1 and 569-2. +ESI-MS: m/z519.1 [M+H]⁺.

Example 318 Preparation of Compound 570

Compound 570 (white solid, 25 mg, 32%) was prepared following thegeneral procedure for preparing 495 using 570-1 and 570-2. +ESI-MS: m/z517.1 [M+H]⁺.

Example 319 Preparation of Compound 571

Compound 571 (white solid, 21 mg, 23%) was prepared following thegeneral procedure for preparing 495 using 571-1 and 571-2. +ESI-MS: m/z517.1 [M+H]⁺.

Example 320 Preparation of Compounds 604a-d

To a mixture of 604-1 (12.0 g, 92.6 mmol) and2,2,2-trifluoroethane-1,1-diol (32.3 g, 277.9 mmol) in H₂O (25 mL) wasadded K₂CO₃ (25.6 g, 185.2 mmol, 2.00 eq.) in one portion at r.t. Theflask was sealed, heated to 125° C. and stirred for 16 h. The mixturewas cooled to 0° C., neutralized with 1M HCl solution, and extractedwith EA (3×100 mL). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas washed with DCM and PE to afford 604-2 (17.0 g, 81%) as a whitesolid.

To a stirring solution of 604-2 (130 g, 571.2 mmol) and Na₂CO₃ (121 g,1.1 mol) in H₂O (800 mL) was added I₂ (174 g, 685.5 mmol) in portions.The mixture was stirred at 25° C. for 48 h. A sat. sodium sulfitesolution (500 mL) was used to quench the reaction. The mixture wasacidified with 3M HCl and diluted with EA (1 L). The organic phase wasseparated, and the aqueous phase was extracted with EA (3×500 mL). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography by using PE:EA=1:1 as the eluent to afford 604-3 (180 g,89%) as a white solid.

To a solution of 604-3 (88 g, 249 mmol) and 1-chloropropan-2-one (55.9g, 605.0 mmol) in DMF (200 mL) was added NaHCO₃ (62.7 g, 746.1 mmol) inone portion at r.t. under N₂. The mixture was stirred at 25° C. for 25h, and the solid was removed by filtration. The filtrate wasconcentrated to dryness under reduced pressure, and the residue wasdissolved in DCM and triturated with PE to afford 604-4 (66 g, 65%) as awhite solid.

A mixture of 604-4 (9.0 g, 22 mmol), 2-methylpropane-2-sulfamide(S-configuration, 2.66 g, 22 mmol) and titanium(IV) ethoxide (10.5 g,46.1 mmol) in anhydrous THF (18.00 mL) was heated to 80° C. (sealedvial, degassed and purged with N₂) and stirred for 1 h. EA (150 mL) andwater (10 mL) were added with stirring. The mixture was stirred for 5mins and filtered through a pad of celite. The filtrate was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel using EA:DCM=1:9 as the eluent to afford604-5 (6.8 g, 60%).

To a solution of EtMgBr (4.4 mL, 13.2 mmol, 3 M in ether) in dry THF (50mL) was added n-BuLi (10.6 mL, 26.5 mmol, 2.5 M in hexane), and themixture was stirred at 0° C. After stirring for 10 mins, the mixture wascooled down to −78° C. A solution of 604-5 (6.8 g, 13.26 mmol) in dryTHF (50 mL) was added dropwise, and the reaction was stirred at −78° C.for 15 mins. The reaction was quenched with H₂O (50 mL) and extractedwith EA (2×100 mL). The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (eluent:0˜10% EA in DCM) to afford 604-6 (3.10 g, 60%).

To a stirring solution of 604-6 (6.8, 17.6 mmol) in DCM (50 mL) wasadded Dess-Martin reagent (8.95 g, 21.1 mmol), and the mixture wasstirred at r.t. under N2 for 1 h. The reaction was quenched with sat.aq. Na₂S03 solution and sat. aq. NaHCO₃ solution. After 30 mins ofstirring vigorously, the organic layers were separated, and the aqueouslayer was extracted with EA (2×100 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (eluent: 0˜10% EA in DCM) to afford 604-7 (5.1 g 75.4%).

To a solution of t-BuOK (1.64 g, 14.58 mmol) in CH₃CN (150 mL) was addedMe₃SOI (3.21 g, 14.58 mmol). The mixture was degassed and stirred atr.t. for 30 mins. The solution containing the ylide was filtered fromthe solid and added to a solution of 604-7 (5.1 g, 13.25 mmol) in CH₃CN(150 mL), which had been previously degassed. The reaction was stirredat r.t. for 1 h. The volatiles were removed under reduced pressure. Theresidue was purified by column chromatography using DCM:EA=9:1 as theeluent to give 604-8 (3.2 g, 60.5%).

To a solution of 604-8 (3.2 g, 8.02 mmol) in MeOH (300 mL) was addedammonia water (10 mL) in one portion. The solution was stirred at 25° C.for 18 h. The volatiles were removed under reduced pressure to affordcrude 604-9 (3.1 g, 93%).

To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (460 mg, 2.17mmol) in DCM (6 mL) was added HATU (985 mg, 2.59 mmol) and DIPEA (558mg, 4.32 mmol) in one portion at r.t. After stirring for 10 mins, 604-9(900 mg, 2.16 mmol) was added. The mixture was stirred for 1 h at r.t.The solution was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (eluent: 10-100% EA in PE) to give604-10 (890 mg, 67.5%).

604-10 (300 mg, 0.49 mmol), (4-cyanophenyl)boronic acid (88 mg, 0.6mmol) and Cs₂C03 (240 mg, 0.74 mmol) were taken up into a microwave tubein co-solvent DME:H₂O (12 mL, v:v=5:1). The solution was degassed andPd(PPh₃)₄ (57 mg, 0.05 mmol, 0.10 eq.) was added. The sealed tube washeated to 110° C. by microwave irradiation and stirred for 1 h. Thesolution was cooled to r.t. and poured into water. The mixture wasextracted with EA (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using EA as the eluent to give 604-11 (320 mg, 96.2%).

To a solution of 604-11 (300 mg, 0.44 mmol) in dioxane (3 mL) was addedHCl/dioxane (1 mL, 4M) at r.t. The mixture was stirred at r.t. until allthe starting material was consumed. The mixture was concentrated underreduced pressure. The residue was dissolved in EA, and basified by asat. NaHCO₃ solution. The organic phase was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto afford crude 604-12 (˜200 mg, 71% yield, 90% purity).

604-12 (˜200.00 mg, 90% purity) was separated by SFC (“Column: ChiralcelOJ-H 250×4.6 mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in C02from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nm”) to give peak1, peak 2, peak 3 and peak 4. The solution of peak 1 in CH₃CN and waterwas treated with HCl (2 M, 0.2 mL) and lyophilized to give 604a (25 mg).+ESI-MS: m/z 573.1 [M+H]⁺. The solution of peak 2 in CH₃CN and water wastreated with HCl (2 M, 0.2 mL) and lyophilized to give 604b (25 mg).+ESI-MS: m/z 573.1 [M+H]⁺. The solution of peak 3 in CH₃CN and water wastreated with HCl (2 M, 0.2 mL) and lyophilized to give 604c (19 mg).+ESI-MS: m/z 573.1 [M+H]⁺. The solution of peak 4 in CH₃CN and water wastreated with HCl (2 M, 0.2 mL) and lyophilized to give 604d (22 mg).+ESI-MS: m/z 573.3 [M+H]⁺.

Example 321 Preparation of Compounds 605a-d

To a solution of 604-10 (400 mg, 0.66 mmol) and (4-fluorophenyl)boronicacid (138 mg, 984 mmol) in DME (3 mL) and H₂O (1 mL) was addedPd(dppf)Cl₂ (24 mg, 0.033 mmol) and Cs₂CO₃ (641 mg, 2.0 mmol) in amicrowave tube under N2. The reaction mixture was heated to 100° C. andstirred for 1 hour. After cooling to room temperature, the reactionmixture was poured into water (30 mL) and stirred for 5 mins. Theaqueous phase was extracted with EA (30 mL×3). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using EA as eluent to give 605-1 (310 mg) as a whitesolid. +ESI-MS: m/z 670.1 [M+H]⁺.

Compounds 605a, 605b, 605c and 605d was prepared following the generalprocedure for preparing 605a using 605-1. The crude was purified byprep-HPLC and SFC separation. 605a (white solid, 20 mg): m/z 566.2[M+H]⁺, 605b (white solid, 18 mg): m/z 566.1 [M+H]⁺, 605c (white solid,12.8 mg): m/z 566.1 [M+H]⁺ and 605d (white solid, 12.7 mg): m/z 566.2[M+H]⁺.

Example 322 Preparation of Compounds 629-632

Compounds 629, 630, 631 and 632 was prepared following the generalprocedure for preparing 605d using 604-10, 629-1 and(4-fluorophenyl)boronic acid. 629 (white solid, 14.1 mg): m/z 580.1[M+H]⁺, 630 (white solid, 18.6 mg): m/z 580.1 [M+H]⁺, 631 (white solid,25.8 mg): m/z 580.1 [M+H]⁺ and 632 (white solid, 34.5 mg): m/z 580.1[M+H]⁺.

Example 323 Preparation of Compounds 633a-633b

633-1 (9.0 g, 25.5 mmol) and NaHCO₃ (6.4 g, 76.4 mmol) were dissolved inDMF (80 mL). 3-bromo-2-methylprop-1-ene (4.5 g, 33.1 mmol) was added bysyringe, and the mixture was heated to 70° C. for 3 h. After cooling tor.t, the reaction was quenched with H₂O and extracted with EA. Theorganic phase was washed with brine, dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (eluent: PE:EA=30:1˜8:1) to give 633-2(8.02 g, 77%) as a white solid. +ESI-MS: m/z 407.8 [M+H]⁺.

A sealed tube was charged with a solution of 633-2 (7.0 g, 17.2 mmol) intoluene (50 mL). Pd₂(dba)₃ (580.0 mg, 1.0 mmol) and Q-phos (1.0 g, 1.4mmol) was added under N₂. The sealed tube was stirred at 100° C. in anoil bath. After stirring for 7 h, the mixture was cooled to r.t. andconcentrated at low pressure. The residue was purified by flashchromatography using 2-5% EA in PE as the eluent to afford 633-3 (3.5 g,50%) as a solid.

To a solution of 633-3 (3.5 g, 8.6 mmol) in DMF (50 mL) was added NaN₃(12.4 g, 190.7 mmol) at r.t. The solution was heated to 70° C. andstirred for 16 h. The mixture was cooled to r.t. and quenched by pouringinto water. The mixture was extracted with EA (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography using 5-12% EA in PE as the eluent togive 633-4 (2.4 g, 86.6%) as an oil. +ESI-MS: m/z 322.9 [M+H]⁺.

633-8 was prepared following the general procedure for preparing 604ausing 633-4.

633-8 (500 mg, 0.92 mmol), (4-fluorophenyl)boronic acid (167 mg, 1.2mmol), Cs₂CO₃ (450 mg, 1.4 mmol) and Pd(PPh₃)₄ (106 mg, 0.092 mmol) weretaken up into a microwave tube in a co-solvent of dioxane (15 mL) andH₂O (3 mL). The sealed tube was heated at 110° C. by microwaveirradiation and stirred for 1 h. LCMS showed that ˜30% of the desiredproduct was formed. The solution was concentrated under reducedpressure, and the residue was purified by TLC and further purified byprep-HPLC to give pure 633a (˜80 mg) and 633b (˜70 mg). 633a: +ESI-MS:m/z 580.2 [M+H]⁺ and 633b: +ESI-MS: m/z 580.1 [M+H]⁺.

Example 324 Preparation of Compound 638

Compound 638 (white solid, 15 mg) was prepared following the generalprocedure for preparing 604a using 604-10 and(3-chloro-4-fluorophenyl)boronic acid. +ESI-MS: m/z 600.1 [M+H]⁺.

Example 325 Preparation of Compounds 653 and 654

2-chloro-4-iodo-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol wasprepared as provided in Hénichart, J. et al., J. Het. Chem. (1986),23(5): 1531-1533.

To a solution of2-chloro-4-iodo-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol (16 g,45.3 mmol) in CH₃CN (150 mL) was added K₂CO₃ (12.5 g, 90.5 mmol) in oneportion. After stirring at r.t. for 5 mins, a solution of 653-3 (9.8 g,54.3 mmol) in CH₃CN (10 mL) was added slowly under N₂. The mixture wasstirred at 90° C. for 1 h in a pre-heated oil bath. After cooling tor.t., the mixture was poured into water (150 mL) and stirred for 5 mins.The mixture was extracted with EA (2×150 mL). The combined organic phasewas washed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography using 2˜5% EA in PE as the eluent to afford 653-4 (10.9g, 49%) as a yellow solid.

653-8 was prepared following the general procedure for preparing 604ausing 653-4.

To a solution of 653-8 (1.0 g, 1.9 mmol) in CH₃NO₂ (15 mL) was added TEA(2.0 mL) in one portion at r.t. The reaction mixture was stirred for 2 hand concentrated under reduced pressure. The residue was purified bycolumn chromatography using 10-20% EA in PE as the eluent to afford653-9 (0.8 g, 72%) as a yellow solid. +ESI-MS: m/z 593.9 [M+H]⁺.

To a solution of 653-9 (400 mg, 0.67 mmol) in EtOH (10 mL) and H₂O (10mL) was added Fe (188 mg, 3.4 mmol) powder and NH₄Cl (180 mg, 3.4 mmol)in one portion. The mixture was stirred at 80° C. for 2 h. After coolingto r.t., the mixture was poured into water (20 mL) and extracted with EA(3×10 mL). The combined organic phase was washed with brine, dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by column chromatography using EA as the eluent to afford653-10 (250 mg, 66%) as a yellow solid. +ESI-MS: m/z 564.1 [M+H]⁺.

To a solution of 4-cyclopropoxy-3-methoxybenzoic acid (75 mg, 0.36 mmol)in DMF (6.0 mL) was added HATU (137 mg, 0.36 mmol) and DIPEA (47 mg,0.36 mmol). After stirring at r.t. for 5 mins, 653-10 (203 mg, 0.36mmol) was added. The mixture was stirred for 1 h and then poured intowater. The mixture was extracted with EA (2×10 mL). The combined organicphase was washed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography using EA as the eluent to afford 653-11 (120 mg, 44.2%)as a yellow solid. +ESI-MS: m/z 754.2 [M+H]⁺.

Ozone was bubbled into a solution of 653-11 (120 mg, 0.16 mmol) inanhydrous MeOH (10 mL) at −78° C. for 6 mins. After excess O3 was purgedby N2, NaBH₄ (18.1 mg, 0.48 mmol) was added at r.t. The reaction wasstirred for 0.5 h and quenched with water. The mixture was extractedwith EA (2×10 mL), dried over sodium sulfate, concentrated to give thecrude product. The residue was purified by column chromatography usingEA as the eluent to afford 653-12 (70 mg, 65%) as a yellow solid.+ESI-MS: m/z 682.1 [M+H]⁺.

To a solution of 653-12 (70 mg, 0.1 mmol) in MeOH (10 mL) was addedHCl/dioxane (3 mL, 4 M). The mixture was stirred at r.t. for 20 mins.The mixture was concentrated under reduced pressure. The residue waspurified by prep-HPLC to afford 653 (12 mg) and 654 (18 mg) as whitesolids. 653: +ESI-MS: m/z 578.1 [M+H]⁺ and 654: +ESI-MS: m/z 578.1[M+H]⁺.

Example 326 Preparation of Compound 606

A mixture of 606-2 (45 mg, 0.1 mmol), 606-1 (16 mg, 0.1 mmol) and TEA (1mmol) is dissolved in anhydrous DCM (4 mL) with stirring. The solutionwas treated with HATU (38 mg, 0.1 mmol) in one portion. After stirringat r.t. for 30 mins, TFA (1 mL) was added. The solution was stirred atr.t. for 2 h. The mixture was concentrated to dryness. The residue wasisolated by acidic prep-HPLC to afford 606 (26 mg, 45%) as a whitesolid. +ESI-MS: m/z 452.0 [M+H]⁺.

Example 327 Preparation of Compound 607

Compound 607 was prepared following the general procedure for preparing606 using 607-1 and 606-2. The crude product was purified by prep-HPLCto give 607 (66 mg, 75%) as a white solid (66 mg, 75%). +ESI-MS: m/z466.9 [M+H]⁺.

Example 328 Preparation of Compound 608

Compound 608 was prepared following the general procedure for preparing606 using 608-1 and 606-2. The crude product was purified by prep-HPLCto give 608 (46.5 mg, 84%) as a white solid. +ESI-MS: m/z 466.9 [M+H]⁺.

Example 329 Preparation of Compound 609

Compound 609 was prepared following the general procedure for preparing606 using 609-1 and 606-2. The crude product was purified by prep-HPLCto give 609 (13.5 mg, 34%) as a white solid. +ESI-MS: m/z 465.9 [M+H]⁺.

Example 330 Preparation of Compound 610

Compound 610 was prepared following the general procedure for preparing606 using 610-1 and 606-2. The crude product was purified by prep-HPLCto give 610 (34 mg, 57%) as a white solid. +ESI-MS: m/z 518.9 [M+H]⁺.

Example 331 Preparation of Compound 613

Compound 613 was prepared following the general procedure for preparing606 using 613-1 and 606-2. The crude product was purified by prep-HPLCto give 613 (29 mg, 50%) as a white solid. +ESI-MS: m/z 451.9 [M+H]⁺.

Example 332 Preparation of Compounds 623a and 623b

To a solution of 623-1 (20 g, 116 mmol) in anhydrous toluene (200 mL)was added MeMgBr (3 M, 115.61 mL) slowly at 0° C. under N₂. Afteraddition and stirring for 30 mins, Ti(i-PrO)₄ (36.1 g, 127.2 mmol) wasadded dropwise The mixture was heated at 100° C. for 30 mins. Aftercooling to r.t., copious quantities of diatomite was added to themixture. The mixture was basified with aqueous NaOH solution (2 M) andfiltered through a pad of diatomite. The cake was washed with EA, andthe filtrate was separated and concentrated to provide crude2-(2,6-dichloro-4-pyridyl)propan-2-amine (˜25 g).

Crude 2-(2,6-dichloro-4-pyridyl)propan-2-amine was dissolved inanhydrous DCM (250 mL). The solution was treated with CbzCl (20.79 g,121.90 mmol) and DIPEA (31.51 g, 243.80 mmol). The mixture was stirredat r.t. overnight. The mixture was washed with brine, dried overanhydrous Na₂SO₄ and concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography using 3˜10% EA in PE asthe eluent to give 623-2 (15 g, 36% yield over 3 steps) as a whitesolid. +ESI-MS: m/z 338.8 [M+H]⁺.

To a stirring solution of 623-2 (5.0 g, 14.7 mmol) in dioxane (100 mL)and water (10 mL) were added (4-cyanophenyl)boronic acid (2.17 g, 14.7mmol), Cs₂CO₃ (9.6 g, 29.5 mmol), and Pd(dppf)Cl₂ (1.08 g, 1.47 mmol)under N2. The mixture was stirred at 80° C. for 1 h under N2. Aftercooling to r.t., the mixture was diluted with EA (100 mL) and water (100mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography using 3-20% EA in PE asthe eluent to give 623-3 (2.0 g, 33% yield) as a white solid.

Compound 623-8 was prepared following the general procedure forpreparing 533 using 623-3. Racemic 623-8 was separated by SFC andprep-HPLC to afford 623a (62 mg) and 623b (29 mg) as white solids. 623a:+ESI-MS: m/z 559.4 [M+H]⁺ and 623b: +ESI-MS: m/z 559.0 [M+H]⁺.

Example 333 Preparation of Compounds 624a and 624b

Compounds 624a (white solid, 62 mg) and 624b (white solid, 62 mg) wereprepared following the general procedure for preparing 623a and 623busing 624-1 and 624-2. 624a: +ESI-MS: m/z 573.1 [M+H]⁺ and 624b:+ESI-MS: m/z 573.1 [M+H]⁺.

Example 334 Preparation of Compound 625

Compound 625 (white solid, 32 mg) was prepared following the generalprocedure for preparing 623a and 623b using 625-1 and 624-2. +ESI-MS:m/z 572.1 [M+H]⁺.

Example 335 Preparation of Compound 634

Compound 634 (white solid, 10 mg) was prepared following the generalprocedure for preparing 406 using 634-1 and 634-2. +ESI-MS: m/z 524.1[M+H]⁺.

Example 336 Preparation of Compound 639

639-6 was prepared as provided in Pascal, R., et al., Eur. J. Org. Chem.(2000) 2000(22):3755-3761.

To a solution of 639-6 (1.1 g, 5.3 mmol) in H₂O (10 mL) was added NaOH(426 mg, 10.7 mmol) in one portion. The mixture was stirred at 25° C.for 17 h. The solid was formed upon acidification to pH 1 withconcentrated HCl (37%). The precipitate was collected by filtration,washed with water and dried in vacuum to give 639-7 (0.5 g, 49%) as awhite solid, which was used for the next step without furtherpurification. +ESI-MS: m/z 193.1 [M+H]⁺.

Compound 639 (28 mg, 45%) was prepared following the general procedurefor preparing 606 using 639-7. +ESI-MS: m/z 532.0 [M+H]⁺.

Example 337 Preparation of Compound 643

To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added2-benzyloxyl ethanol (6.3 g, 41 mmol) at 25° C. The solution was stirredfor 6 h and then poured into H₂O (20 mL). The mixture was extracted withEA (2×40 mL). The combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography using 5˜10% EA in PE asthe eluent to give a mixture of 643-2 and 643-2A (1.50 g).

To a solution of 643-2A and 643-2A (1.50 g, crude mixture) in EtOH/H₂O(20/10 mL) were added Fe (1.5 g, 26.7 mmol) and NH₄Cl (1.5 g, 28 mmol)at 25° C. The solution was heated to 80° C. and stirred for 2 h. Themixture was filtered, and the filtrate was concentrated to give amixture of 643-3 and 643-3A (1.20 g, crude). The products were used forthe next step without further purification.

A mixture of 643-3 and 643-3A (1.2 g, crude) in H₂SO₄/H₂O (1:1) (10 mL)was cooled to −5° C. NaNO₂ (376 mg, 5.45 mmol) was added in portions at−5° C. The solution was stirred at −5° C. for 0.5 h. The solution washeated to 120° C. After stirring 0.5 h at 120° C., the solution waspoured into ice water (20 mL) and extracted with EA (2×20 mL). Theorganic phase was concentrated at low pressure. The residue was purifiedby chromatography to give 643-4 (0.3 g, crude).

To a solution of 643-4 (0.3 g, crude) in DMF (5 mL), K₂CO₃ (320 mg, 2.3mmol) was added dropwise CH₃I (2.14 g, 15.1 mmol) at r.t. The solutionwas stirred for 3 h. The mixture was poured into H₂O (10 mL) andextracted with EA (2×20 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give crude 643-5 (210 mg), which was used in the next stepdirectly.

To a mixture of 643-5 (210 mg, crude) in MeOH (2 mL) was added an aq.NaOH solution (2 mL, 2 M) in one portion at 25° C. The mixture washeated to 60° C. and stirred for 2 h. The mixture was cooled to r.t. andacidified to pH=3˜4 by the addition of 1 M aqueous HCl. The mixture wasextracted with EA (3×10 mL). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC (EA) to afford 643-6 (110mg, 56%).

Compound 643 (white solid, 14 mg, 24%) was prepared following thegeneral procedure for preparing 606 using 643-6. +ESI-MS: m/z 553.1[M+H]⁺.

Example 338 Preparation of Compound 644

644-2 was prepared as provided in PCT Publication No. WO 2013/007663,published Jan. 17, 2013.

644-4 was prepared following the general procedure for preparing 272using 644-2.

A mixture of 644-4 (1.5 g, 5.5 mmol), potassium vinyl trifluoroborate(1.6 g, 11.1 mmol), Cs₂CO₃ (1.8 g, 5.5 mmol) and Pd(dppf)Cl₂ (0.4 g, 0.5mmol) in i-PrOH (10 mL) was de-gassed. The mixture was heated to 80° C.for 15 h under N2. After cooling to r.t, the mixture was concentratedunder reduced pressure. The residue was purified by columnchromatography using 5-20% DCM in PE to give 644-5 (0.9 g, 74.5%).

Ozone was bubbled into a solution of 644-5 (0.87 g, 4 mmol) in anhydrousMeOH (10 mL) at −78° C. for 10 mins. After the excess ozone was purgedby N2, NaBH₄ (304 mg, 8 mmol) was added at 25° C. The solution wasstirred at 25° C. for 30 mins. The reaction was quenched with H₂O andextracted with EA (3×20 mL). The combined organic solutions were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography 10-25% DCMin PE to give 644-6 (0.7 g, 79%) as a solid.

To a solution of 644-6 (0.5 g, 2.3 mmol) in MeOH (3 mL) was added NaOH(0.5 g, 12.5 mmol) in H₂O (3 mL). After stirring at 60° C. for 1 h, themixture was acidified to pH=3˜4 by addition of 2 M HCl solution. Themixture was extracted with EA (3×10 mL). The combined organic solutionswere washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to give 644-7 (0.4 g, 85.3%).

Compound 644 (while solid, 27 mg, 42%) was prepared following thegeneral procedure for preparing 606 using 644-7. +ESI-MS: m/z 548.0[M+H]⁺.

Example 339 Preparation of Compound 657

657-6 was prepared following the general procedure for preparing 606using 657-1.

To a stirring solution of 657-6 (2 g, 4.3 mmol) in EtOH (40 mL) wereadded SnCl₂ 2H₂O (3.9 g, 17.3 mmol) and cone. HCl (5.4 mL, 12 M). Afterstirring at 60° C. for 12 h, the mixture was cooled to r.t., and EtOHwas removed under reduced pressure. The residue was diluted with water(10 mL) and neutralized by sat. aq. Na₂CO₃ solution. The aqueous phasewas extracted with EA (3×30 mL). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing 50-100% EA in PE as the eluent to afford 657-7 (0.82 g, 44%) as ayellow oil. +ESI-MS: m/z 432.3 [M+H]⁺.

To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (1.5 g, 7.2mmol) in anhydrous DMF (30 mL) were added HATU (2.7 g, 7.2 mmol) andDIEA (2.3 g, 18 mmol). After stirring at 25° C. for 30 mins, a solutionof 657-7 (2.5 g, 6.0 mmol) in DMF (5 mL) was added dropwise. The mixturewas stirred at 25° C. for 1-2 h. The solution was poured into water (50mL), and extracted with EA (3×30 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using DCM:MeOH=200:1˜80:1 as the eluent to afford 657-8(2.2 g, 59%) as yellow oil.

657-8 (100 mg, 0.16 mmol), 4-Cl-phenyl boronic acid (50 mg, 0.32 mmol)and Cs₂CO₃ (156 mg, 0.48 mmol) were taken up into a microwave tube inco-solvent dioxane:H₂O (1.2 mL, v:v=5:1). The solution was degassed andPd(dppf)Cl₂ (3.5 mg, 0.05 mmol) was added. The sealed tube was heated to110° C. by microwave irradiation and stirred for 1 h. The solution wascooled to r.t. and poured into water (10 mL). The mixture was extractedwith EA (3×5 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purification by prep-TLC to give 657-9 (49 mg,44%)

To a solution of 657-9 (49 mg) in CH₃CN (1 mL) was added one drop ofTMSI at r.t., and the mixture stirred at r.t. for 10 mins. The mixturewas poured into water, neutralized with sat. NaHCO₃ solution, andextracted with EA (3×10 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC to give 657 (15mg) as a white solid. +ESI-MS: m/z 567.9 [M+H]⁺.

Example 340 Preparation of Compound 658

Compound 658 (white solid, 8 mg) was prepared following the generalprocedure for preparing 657 using 658-1 and 4-CF₃-phenyl boronic acid.The crude product was purified by prep-HPLC. +ESI-MS: m/z 602.1 [M+H]⁺.

Example 341 Preparation of Compound 659

Compound 659 (white solid, 11 mg) was prepared following the generalprocedure for preparing 657 using 659-1 and 2-methoxy-4-pyridyl boronicacid. The crude product was purified by prep-HPLC. +ESI-MS: m/z 565.1[M+H]⁺.

Example 342 Preparation of Compound 660

Compound 659 (white solid, 10 mg) was prepared following the generalprocedure for preparing 657 using 660-1 and 2-methoxy-4-pyridyl boronicacid. The crude product was purified by prep-HPLC. +ESI-MS: m/z 565.1[M+H]⁺.

Example 343 Preparation of Compound 614

A mixture of 614-1 (23 mg, 0.1 mmol), 614-2 (50 mg, 0.1 mmol) and TEA (1mmol) were dissolved in DCM (4 mL). HATU (38 mg, 0.1 mmol) was added,and the mixture was stirred for 30 mins. The mixture was diluted withbrine (5 mL), and the aqueous phase was extracted with DCM (2×5 mL). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue wasdissolved in MeOH (10 mL) and hydrogenated over Pd/C (10 mg, 10%) at 15psi for 17 h. The catalyst was removed by filtration, and the cake waswashed with MeOH (5 mL). The combined filtrates was concentrated andpurified by prep-HPLC to give 614 (28 mg, 45%). +ESI-MS: m/z 584.0[M+H]⁺.

Example 344 Preparation of Compound 615

Compound 615 (white solid, 43 mg) was prepared following the generalprocedure for preparing 614 using 615-1 and 615-2. The crude product waspurified by prep-HPLC. +ESI-MS: m/z 583.1 [M+H]⁺.

Example 345 Preparation of Compound 626

To a solution of 540 (160 mg, 0.26 mmol) in MeOH (2 mL) was added Pd/C(150 mg) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred at 25° C. for 12 h. Themixture was filtered through a pad of Celite, and the pad was washedwith MeOH. The combined filtrates were concentrated under reducedpressure. The residue was purified by prep-HPLC of acidity with HCl togive 626 (69 mg, 43%). +ESI-MS: m/z 570.0 [M+H]⁺.

Example 346 Preparation of Compound 627

A mixture of 627-1 (66 mg, 0.3 mmol), 627-2 (150 mg, 0.3 mmol) and TEA(1 mmol) were dissolved in DCM (4 mL). HATU (120 mg, 0.2 mmol) wasadded, and the mixture was stirred for 30 mins. The reaction was dilutedwith brine (5 mL), and the aqueous phase was extracted with DCM (2×5mL). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give crude627-2, which was used in next step without further purification.+ESI-MS: m/z 764.1 [M+H]⁺.

To a solution of 627-2 (0.7 g, crude) in MeOH (20 mL) was added LiBH₄(59 mg, 2.8 mmol) in one portion at r.t. The mixture was stirred for 1h. The reaction was quenched with 2N HCl solution and extracted with EA(3×20 mL). The combined organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography using PE:EA=30:1˜3:1 as the eluentto afford 627-3 (0.6, 89%) as an oil. +ESI-MS: m/z 736.0 [M+H]⁺.

Compound 627 (white solid, 180 mg) was prepared following the generalprocedure for preparing 540 using 627-3. +ESI-MS: m/z 568.1 [M+H]⁺.

Example 347 Preparation of Compounds 655 and 656

Compound 615 (30 mg) was separated by SFC to give solutions of peak 1and peak 2. The two peaks were acidified by aq. HCl (2 M) andlyophilized to give 655 (9.2 mg) and 656 (8.9 mg) as a white solid. 655:+ESI-MS: m/z 583.1 [M+H]⁺ and 656: +ESI-MS: m/z 583.1 [M+H]⁺.

Example 348 Preparation of Compound 622

622-1 (white solid, 610 mg) was prepared following the general procedurefor preparing 536. +ESI-MS: m/z 760.1 [M+H]⁺.

Compound 622 (12 mg) was prepared following the general procedure forpreparing 581 using 622-1. LCMS: m/z 592.15 [M+H]⁺.

Example 349 Preparation of Compound 650

650-17 (white solid, 210 mg) was prepared following the generalprocedure for preparing 563 using 650-1 and 4-F-phenyl boronic acid.+ESI-MS: m/z 698.1 [M+H]⁺.

To a stirring mixture of 650-17 (200 mg, 0.28 mmol) in CH₃CN (2 mL) wereadded NaI (215 mg, 1.4 mmol) and TMSCl (152 mg, 1.4 mmol). The mixturewas stirred at 65° C. for 20 mins. The mixture was cooled to r.t. anddiluted with EtOAc. The reaction was quenched with a 10% aqueoussolution of Na₂S₂O₃. The layers were separated, and the aqueous layerwas extracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct mixture was purified via prep-HPLC to afford 650 (10 mg) as awhite solid. LCMS 564.20 m/z [M+H]⁺.

Example 350 Preparation of Compound 667

To a solution of 667-1 (100 mg, 0.16 mmol) in THF (1 mL) was addedcyclopropylmagnesium chloride (2 mL, 1 mmol) dropwise at r.t. Themixture was stirred for 2 h. The reaction was quenched with aq. NH₄Cland extracted with EA (3×10 mL). The combined organic phase was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by prep-TLC (PE:EA=1:1) to give 667-2 (62 mg,58.4%).

To a solution of 667-2 (62 mg, 0.1 mmol) in DCM (2 mL) was added TFA (2mL) at r.t. The mixture was stirred for 30 mins. The mixture wasneutralized by aq. NaHCO₃ solution and extracted by EA (3×10 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 667 (9 mg, 16.3%) as a white solid. +ESI-MS: m/z 554.0[M+H]⁺.

Example 351 Preparation of Compound 603

Enantiomer 603-2 (270 mg) was obtained by SFC separation of racemic603-1 (1.1 g).

To a stirring mixture of 603-2 (270 mg 0.8 mmol) in 2-methylpropan-2-ol(6 mL):H₂O (2 mL) at 0° C. were added BocN-OTs (308 mg 1.07 mmol) andK₂OsO₄.H₂O (60 mg, 0.16 mmol) at r.t. The mixture was stirred at r.t.for 30 h. The mixture was diluted with water and extracted with DCM(3×10 mL). The combined organic phase was washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography using PE:EA=1:1 as the eluent to afford 603-3(˜200 mg, ˜60%). +ESI-MS: m/z 638.1 [M+H]⁺.

To a mixture of 603-3 (200 mg, 0.32 mmol) in DCM (6 mL) was added TFA (3mL) at r.t. The mixture was stirred for 30 mins, neutralized withaqueous NaHCO₃ and extracted with EA (3×10 mL). The combined organiclayers were washed by brine, dried over Na₂SO₄ and concentrated underreduced pressure to give crude 603-4 (110 mg), which was used withoutfurther purification. +ESI-MS: m/z 538.1 [M+H]⁺.

To a solution of 4-(cyclopropoxy)-3-methoxy-benzoic acid (37 mg, 0.17mmol), HATU (100 mg 0.26 mmol) and DIPEA (57 mg, 0.44 mmol) in anhydrousDMF (3 mL) was added 603-4 (110 mg crude) at r.t. The solution wasstirred for 5 h at r.t. with TLC monitoring. The mixture was dilutedwith 1.0 N aqueous NaHCO₃ solution and extracted with EA (3×10 mL). Thecombined organic layers were washed by brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography using PE:EA=1:1 as the eluent andprep-HPLC to give 603-5 (43 mg, 28.7%). +ESI-MS: m/z 728.1 [M+H]⁺.

To a stirring mixture of 603-5 (15 mg, 0.041 mmol) in CH₃CN (1 mL) atr.t. were added NaI (32 mg, 0.2 mmol) and TMSCl (22 mg, 0.2 mmol). Themixture was stirred at 55° C. for 15 mins. The mixture was diluted withEtOAc and washed with a 10% aq. Na₂S₂O₃ solution. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The reaction was concentrated and the crude productwas purified by prep-HPLC to provide 603. +ESI-MS: m/z 594.20 [M+H]⁺.

Example 352 Preparation of Compound 575

Cyclobutanone (17 μL, 0.22 mmol) and sodium cyanoborohydride (47 mg,0.22 mmol) were added to a solution of 314 (43 mg, 0.074 mmol) every 30mins for 6 h. The mixture was diluted with EtOAc, washed with 1N HCl andbrine, dried over MgSO₄ and concentrated under reduced pressure. Thecrude product was purified by reverse phase HPLC to give 575 (14 mg,23%). LCMS: m/z 637.20 [M+H]⁺.

Example 353 Preparation of Compound 577

Compound 577 was prepared following the general procedure for preparing575. LCMS: m/z 639.10 [M+H]⁺.

Example 354 Preparation of Compound 581

577 (12 mg, 0.019 mmol) was hydrogenated over 10% Pd/C (3 mg) in EtOH (2mL) for 1 h. The catalyst was removed by filtration and the crudeproduct was purified by reverse-phase HPLC to give 581 (8 mg, 66%).LCMS: m/z 604.20 [M+H]⁺.

Example 355 Preparation of Compound 576

Pd(dppf)Cl₂ (66 mg, 0.091 mmol) was added to a solution of2,4-dichloro-4-iodopyridine (0.50 g, 1.8 mmol),(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid(0.54 g, 1.8 mmol) and cesium carbonate (1.8 g, 5.5 mmol) indimethoxyethane (10 mL) and water (1 mL). The mixture was heated undermicrowave irradiation at 110° C. for 1 h. The mixture was diluted withEA, washed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give576-1 (0.47 g, 72%). LCMS: m/z 329.00 [M+H]⁺.

A solution of 576-1 (0.83 g, 2.5 mmol) and platinum oxide (83 mg) inEtOH was stirred under H₂ atmosphere for 1 h. The mixture was filteredto remove catalyst and concentrated. The product (0.80 g, 96%) was usedwithout further purification. LCMS: m/z 331.05 [M+H]⁺.

HCl (4N in dioxane, 3 mL) was added to 576-2 (0.80 g, 2.4 mmol). Themixture was stirred at r.t. for 30 mins and concentrated under reducedpressure. The crude product was dissolved in CH₂Cl₂ (10 mL), and DIEA(1.1 mL, 6.0 mmol) and benzyl chloroformate (0.41 mL, 2.9 mmol) wereadded. The reaction was stirred at r.t. for 1 h. The mixture was dilutedwith EA, washed with 1N HCl and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 576-3 (0.49 g, 54%). LCMS: m/z 365.05 [M+H]⁺.

Pd(dppf)Cl₂ (0.45 g, 0.61 mmol) was added to a solution of 576-3 (0.49g, 1.3 mmol), 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester(0.30 g, 1.3 mmol), Cs₂CO₃ (1.3 g, 4.0 mmol) in DME (3 mL) and water(0.3 mL). The reaction vessel was heated under microwave irradiation for20 mins at 110° C. The mixture was diluted with EA. The organic phasewas washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 576-4 (0.23 g, 41%). LCMS: m/z 425.05 [M+H]⁺.

Pd(dppf)Cl₂ (20 mg, 0.027 mmol) was added to a solution of 576-4 (0.23g, 0.54 mmol), 3-chloro-4-fluorophenyl boronic acid (95 mg, 0.54 mmol),Cs₂CO₃ (0.53 g, 1.6 mmol) in DME (2 mL) and water (0.2 mL). The reactionvessel was heated under microwave irradiation at 110° C. for 1 h. Themixture was diluted with EA. The organic phase was washed with water andbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel (EA:hexane) to give 576-4 (0.11g, 38%). LCMS: m/z 519.10 [M+H]⁺.

Potassium osmate (11 mg, 0.029 mmol) was added to a solution of 576-5(0.11 g, 0.21 mmol) and tert-butyl (tosyloxy)carbamate (91 mg, 0.33mmol) in t-butanol (1 mL) and water (0.33 mL). The solution was stirredovernight at r.t. The crude mixture was purified by chromatography onsilica gel (EA:hexane) to give 576-6 (0.12 g, 85%). LCMS: m/z 652.20[M+H]⁺.

HCl (2 mL, 4N in dioxane) was added to 576-6 (0.12 g, 0.18 mmol), andthe mixture was stirred at r.t. for 2 h. The solvent was removed byevaporation and the amine salt was re-dissolved in DMF (1 mL).4-cyclopropoxy-3-methoxybenzoic acid (57 mg, 0.28 mmol), HATU (0.14 g,0.37 mmol) and DIEA (0.14 mL, 0.74 mmol) were added, and the mixture wasstirred at r.t. for 2 h. The mixture was diluted with EA. The organicphase was washed with 1N HCl, water and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel (EA:hexane) to give 576-7 (35 mg, 26%). LCMS: m/z 742.20[M+H]⁺.

Chlorotrimethylsilane (23 μL, 0.24 mmol) was added dropwise to asolution of 576-7 (35 mg, 0.047 mmol) and NaI (28 mg, 0.24 mmol) inCH₃CN (1 mL), and the mixture was stirred for 30 mins. The mixture wasdiluted with EA, washed with Na₂S₂O₃ and brine, dried and concentrated.The crude product was purified by reverse-phase HPLC to provide 576 (13mg, 37%). LCMS: m/z 609.15 [M+H]⁺.

Example 356 Preparation of Compound 579

Ethyl acetamidate hydrochloride (150 mg, 1.2 mmol) was added to asolution of 314 (50 mg, 0.086 mmol) in EtOH (3 mL). The mixture heatedat reflux for 24 h. The mixture was diluted with EA, washed with brine,dried and concentrated. The crude product was purified by reverse phaseHPLC to give 579 (8 mg, 16%). LCMS: m/z 624.15 [M+H]⁺.

Example 357 Preparation of Compound 585

Compound 585 was prepared following the general procedure for preparing579 using 318 and ethyl acetamidate. LCMS: m/z 590.20 [M+H]⁺.

Example 358 Preparation of Compound 580

Benzyl(2-2(3-amino-1,1,1-trifluoro-2-hydroxypropan-2-yl)-6-(3-chloro-4-fluorophenyl)pyridine-4-yl)propan-2-yl)carbamatewas coupled with 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid followingthe general procedure for 576-7. 580-1 was hydrogenated following thegeneral procedure for preparing 581. LCMS: m/z 565.15 [M+H]⁺.

Example 359 Preparation of Compound 586

586-1 was prepared following the general procedure for 576-7. HCl indioxane (3 mL) was added to 568-1 (92 mg, 0.18 mmol), and the mixturewas stirred at r.t. for 3 h. The mixture was concentrated, and the crudeproduct purified by reverse-phase HPLC to provide 586 (43 mg, 47%).LCMS: m/z 566.20 [M+H]⁺.

Example 360 Preparation of Compound 592

Compound 592 was prepared following the general procedure for 586 using4-acetamido-3-methoxybenzoic acid. LCMS: m/z 583.15 [M+H]⁺.

Example 361 Preparation of Compound 593

Compound 593 was prepared following the general procedure for 586. LCMS:m/z 619.00 [M+H]⁺.

Example 362 Preparation of Compound 596

Compound 596 was prepared following the general procedure for 586 using4-(3-hydroxycyclobutoxy)-3-methoxybenzoic acid. LCMS: m/z 578.20 [M+H]⁺.

Example 363 Preparation of Compound 616

To a stirring mixture of methyl 4-hydroxy-3-methoxybenzoate (1 g, 5.49mmol) in DMF (5 mL) at r.t. were added K₂CO₃ (1.14 g, 8.24 mmol) and2-bromoacetonitrile. The mixture was stirred at r.t. for several hoursand then diluted with EtOAc and water. The layers were separated, andthe aqueous layer was extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product mixture was purified via asilica gel chromatography to afford 616-1 as a white solid.

To a stirring mixture of 616-1 (190 mg, 0.856 mmol) in DMF (2 mL) wereadded NaN₃ (71.5 mg, 1.1 mmol) and NH₄Cl (59 mg, 1.1 mmol). The mixturewas carried out under microwave irradiation for 45 mins at 100° C. Themixture was diluted with EtOAc and water, and the layers were separated.To the aqueous layer was added a 10% aqueous HCl solution until a whiteprecipitation was formed. The tetrazole-product was filtered off, andthen dissolved directly in aq. NaOH solution (1.5 mL, 2N). The mixturewas heated at 80° C. for 30 mins. The mixture was cooled to r.t. andacidified with a 10% aq. HCl solution. The white solid was filtered offand dry under reduced pressure. Crude 616-2 was used without furtherpurification. LCMS: m/z 265.05 [M+H]⁺.

Compound 616 was prepared following the general procedure for 586 using616-2. LCMS: m/z 624.15 [M+H]⁺.

Example 364 Preparation of Compound 599

599-1 was prepared following the general procedure for 576-7.Pd(dppf)Cl₂ (12 mg, 0.016 mmol) was added to a solution of 599-1 (0.23g, 0.32 mmol), pyridine-4-boronic acid (65 mg, 0.016 mmol) and cesiumcarbonate (0.31 g, 0.96 mmol) in dimethoxyethane (2 mL) and water (0.2mL). The mixture was heated under microwave irradiation at 110° C. for20 mins. The mixture was diluted with EA, washed with brine, dried andconcentrated. The residue was purified by chromatography on silica gel(EA:hexane) to give 599-2 (0.11 g, 50%).

599-2 was prepared following the general procedure for 586 to give 599.LCMS: m/z 569.20 [M+H]⁺.

Example 365 Preparation of Compound 601

DIEA (87 μL, 0.50 mmol) was added to a solution of 317 (0.10 g, 0.16mmol), acetic acid (20 mL, 0.33 mmol) and HATU (0.14 g, 0.35 mmol) inDMF. The mixture was stirred at r.t. for 1 h. The crude product waspurified by reverse phase HPLC to provide 601 (17 mg, 17%). LCMS: m/z642.15 [M+H]⁺.

Example 366 Preparation of Compound 611

Compound 611 was prepared following the general procedure for 601 using320. LCMS: m/z 594.20 [M+H]⁺.

Example 367 Preparation of Compound 612

Compound 612 was prepared following the general procedure for 601 using322. LCMS: m/z 641.15 [M+H]⁺.

Example 368 Preparation of Compound 621

Compound 621 was prepared following the general procedure for 601 using580. LCMS: m/z 607.20 [M+H]⁺.

Example 369 Preparation of Compound 620

Compound 620 was prepared following the general procedure for 601 using586. LCMS: m/z 608.2 [M+H]⁺.

Example 370 Preparation of Compound 595

Isopropylmagnesium chloride (2M in THF, 2.0 mL, 4.0 mmol) was addeddropwise to a solution of 2,6-dichloro-4-iodopyridine (1.0 g, 3.7 mmol)at −40° C. The solution was stirred for 30 mins. 3-Oxetanone (0.28 mL,4.4 mmol) was added dropwise. The mixture was stirred and warmed to r.t.for 2 h. The reaction was quenched with 1N HCl, extracted with EA,washed with brine, dried and concentrated. The residue was purified bychromatography on silica gel (EA:hexane) to give 595-1 (0.42 g, 51%).

Methanesulfonylchloride (1.1 mL, 15 mmol) was added dropwise to asolution of 595-1 (2.14 g, 9.7 mmol) and diisopropylethylamine (3.4 mL,19 mmol) in CH₂Cl₂. The mixture was stirred at 0° C. for 1 h. Themixture was washed with 1N HCl and brine, dried and concentrated. Theresidue was purified by chromatography on silica gel (EA:hexane) to give595-2 (1.91 g, 66%).

Sodium azide (0.83 g, 1.3 mmol) was added to a solution of 595-2 (1.91g, 0.64 mol) in DMSO (3 mL), and the mixture was stirred at 70° C. for 2h. The mixture was diluted with EA, washed with water and brine, driedand concentrated. The product was purified by chromatography on silicagel (hexane:EA) to provide 595-3 (0.67 g, 42%).

Trimethylphosphine (1M in THF, 2.2 mL, 2.2 mmol) was added to a solutionof 595-3 (0.357 g, 1.5 mmol) in EA (5 mL). The mixture was stirred for20 mins. Water (0.5 mL) was added, and the mixture was stirred at 70° C.for 1 h. The mixture was washed with brine, dried and concentrated toprovide 595-4 (0.31 g, 93%) which was used without further purification.

Benzyl chloroformate (0.98 mL, 6.9 mmol) was added to a solution of595-4 (4.6 mmol) in THF (15 mL) and sat. sodium carbonate (15 mL). Themixture was stirred at r.t. overnight, and the aqueous layers wereseparated. The organic layer was washed with brine, dried andconcentrated. The product was purified by chromatography on silica gel(hexane:EA) to provide 595-5 (1.4 g, 87%).

Compound 595-6 was prepared following the general procedure for 576-4.LCMS: m/z 413.05 [M+H]⁺. Compound 595-7 was prepared following thegeneral procedure for 576-5. LCMS: m/z 473.10 [M+H]⁺. Compound 595-8 wasprepared following the general procedure for 576-6. LCMS: m/z 606.15[M+H]⁺.

595-8 (75 mg, 0.12 mmol) was dissolved in hexafluoroisopropanol (1.5mL). The solution was heated under microwave irradiation at 150° C. for65 mins. The mixture was concentrated, and crude 595-9 was used withoutfurther purification. LCMS: m/z 505.46 [M+H]⁺.

595-10 was prepared following the general procedure for 576-7. LCMS: m/z696.20 [M+H]⁺. Compound 595 was prepared following the general procedurefor 580 using 595-10. LCMS: m/z 562.15 [M+H]⁺.

Example 371 Preparation of Compound 602

Benzyl chloroformate (0.61 mL, 4.3 mmol) was added dropwise to asolution of 602-1 (0.86 g, 2.9 mmol) and diisopropylethylamine (1.0 mL,5.7 mmol) in CH₂Cl₂ (10 mL). The mixture was stirred at r.t. overnight.The mixture was washed with 1N HCl and brine, dried and concentrated.Crude 602-2 (0.73 g, 58%) was purified by chromatography (hexane:EA).LCMS: m/z 433.05 [M+H]⁺.

602-3 was prepared following the general procedure for 576-4. LCMS: m/z439.10 [M+H]⁺. 602-4 was prepared following the general procedure for576-6. LCMS: m/z 572.15[M+H]⁺. 602-5 was prepared following the generalprocedure for 576-7. LCMS: m/z 679.20 [M+H]⁺. Compound 602 was preparedfollowing the general procedure for 580 using 602-5. LCMS: m/z 511.15[M+H]⁺.

Example 372 Preparation of Compound 578

Trifluoroacetic acid (0.3 mL) was added to 578-1 (55 mg, 0.069 mmol) inCH₂Cl₂, and the mixture was stirred at r.t. for 4 mins. The reaction wasquenched with cold sodium bicarbonate and extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine, dried, concentratedand used without further purification.

Potassium carbonate (50 mg, 0.35 mmol) was added to a solution of 578-2(0.069 mmol) and tert-butyl bromoacetate (30 μL, 0.21 mmol) in DMF (1mL). The mixture was heated at 55° C. for 1 h. The mixture was dilutedwith EA, and washed with water and brine. The crude product was purifiedby column chromatography (hexane:EA) to provide 578-3. LCMS: m/z 790.20[M+H]⁺.

Compound 578 was prepared following the general procedure for 576 using578-3. LCMS: m/z 600.15 [M+H]⁺.

Example 373 Preparation of Compound 619

619-1 was prepared following the general procedure for 576. Compound 619was prepared following the general procedure for 580. LCMS: m/z 525.15[M+H]⁺.

Example 374 Preparation of Compound 635

DIEA (90 μL, 0.52 mmol) was added to a solution of 635-1 (72 mg, 0.17mmol), 8-methoxyquinoline-6-carboxylic acid (45 mg, 0.21 mmol) and HATU(98 mg, 0.26 mmol). The mixture was stirred at r.t. for 2 h. The mixturewas purified by reverse-phase HPLC to provide 635-2 (50 mg, 48%). LCMS:m/z 601.10 [M+H]⁺.

Pd(dppf)Cl₂ (3 mg, 0.0041 mmol) was added to a solution of 635-2 (50 mg,0.083 mmol), 4-fluorophenyl boronic acid (17 mg, 0.12 mmol), K₃PO₄ (0.11mg, 0.22 mmol), KH₂PO₄ (45 mg, 0.22 mmol) in DME (1 mL), EtOH (0.6 mL)and water (0.2 mL). The solution was heated under microwave irradiationat 110° C. for 4 h. The mixture was diluted with EA, washed with brine,dried and concentrated. Crude 635-3 was purified by silica gelchromatography (MeOH:EtOAc). LCMS: m/z 661.20 [M+H]⁺.

635-3 (27 mg) was dissolved in MeOH (1 mL). To this stirring mixture wasadded a solution of HCl in dioxane (0.2 mL). The mixture was stirred atr.t. for 5 mins. The mixture was concentrated, and 635 (5 mg, 25%) waspurified by reverse-phase HPLC. LCMS: m/z 557.15 [M+H]⁺.

Example 375 Preparation of Compound 637

Chloromethanesulfonyl chloride (0.4 mL, 4.4 mmol) was added dropwise toa solution of ammonia (0.5 M in dioxane, 8.8 mL, 4.4 mmol) and DIEA(0.92 mL, 5.3 mmol) at 0° C. The solution was stirred for 1 h. Thereaction was washed with 1N HCl and brine, dried and concentrated. Thecrude product was used without further purification.

Potassium carbonate (1.2 g, 8.8 mmol) was added to a solution of methylvanillate (0.40 g, 2.2 mmol) and 637-1 (4.4 mmol) in DMF (2.0 mL). Themixture was stirred at 65° C. overnight. The reaction was diluted withEA, washed with water and brine, dried and concentrated. The crudeproduct was purified by silica gel chromatography (hexane:EA) to provide637-2 (50 mg, 8%).

NaOH (2N, 1 mL) was added to a solution of 637-2 (50 mg, 0.18 mmol) inMeOH (3 mL). The mixture was stirred at r.t. overnight. The mixture wasacidified by the addition of 2N HCl and extracted with EA. The organicextracts were washed with brine, dried and concentrated. Crude 637-3 wasused without further purification.

637-4 was prepared following the general procedure for 576-7. Compound637 was prepared following the general procedure for 586. LCMS: m/z635.15 [M+H]⁺.

Example 376 Preparation of Compound 618

Cesium carbonate (1.0 g, 5.9 mmol) as added to vanillic acid (2.0 g, 12mmol) suspended in 90% aq. MeOH (20 mL). The mixture was stirred at r.t.for 30 mins. The solvents were removed and the crude product was driedby co-evaporating (2×) with toluene. The cesium salt was re-dissolved inDMF (15 mL). Benzyl bromide was added, and the mixture was stirred atr.t. overnight. The mixture was diluted with EA, washed with water andbrine, dried and concentrated. The product was purified by silica gelchromatography (hexane:EA) to yield 618-1 (0.4 g, 12%).

Ethyl bromoacetate (0.34 mL, 3.1 mmol) was added to a solution of 618-1(0.4 g, 1.5 mmol) and potassium carbonate (0.64 g, 4.6 mmol) in DMF (3mL). The mixture was stirred at r.t. for 3 h. The mixture was washedwith water and brine, dried and concentrated. The crude product waspurified by column chromatography (hexane:EA) to yield 618-2 (0.177 g,34%).

618-2 (0.177 g 0.51 mmol) was hydrogenated over 10% Pd/C (35 mg) in EtOHfor 45 mins. The catalyst was removed by filtration, and the mixture wasconcentrated to yield 618-3 (0.13 g, 100%), which was used withoutfurther purification.

618-4 was prepared following the general procedure for 576-7. LCMS: m/z728.20 [M+H]⁺. NaOH (2N, 2 mL) was added to a solution of 618-4 (0.302g, 0.43 mmol) in MeOH (10 mL). The mixture was stirred overnight at r.t.The mixture was acidified with 1N HCl and extracted with EA. The organicextracts were washed with brine, dried and concentrated to yield 618-5(0.29 g, 92%). LCMS: m/z 700.20 [M+H]⁺.

DMAP was added to a solution of 618-5 (50 mg, 0.071 mmol), methylsulfonamide (10 mg, 0.11 mmol) and EDCI (16 mg, 0.086 mmol) in DMF (1mL). The mixture was stirred at r.t. overnight. The product was purifiedby reverse-phase HPLC to yield 618-6 (27 mg). LCMS: m/z 777.05 [M+H]⁺.Compound 618 was prepared following the general procedure for 586. LCMS:m/z 677.05 [M+H]⁺.

Example 377 Preparation of Compound 617

Compound 617 was prepared following the general procedure for 586. LCMS:m/z 628.15 [M+H]⁺.

Example 378 Preparation of Compound 641

To a stirring mixture of 641-1 (950 mg, 1.9 mmol) in t-BuOH:water (3:1,3 mL total volume) at r.t. were added potassium osmate dihydrate (105mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). Themixture was stirred at r.t. overnight. The mixture was diluted withwater and DCM. The aqueous layer was extracted with DCM, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a silica gel chromatography to afford 641-3 asa minor product (200 mg, 10%); LCMS: m/z 527.2 [M+H]⁺.

tert-butyl tosyloxycarbamate was prepared as follows. To a stirringmixture of tert-butyl hydroxy carbamate (2 g, 15 mmol) in THF (10 mL) at0° C. was added TsCl (2.8 g, 15 mmol) and TEA (2.2 mL, 15.8 mmol). Themixture was stirred at 0° C. for 20 mins and then quickly warmed to r.t.for 5 mins. The mixture was diluted with DCM and washed with water. Anaqueous workup with DCM gave the crude product, which was purified via asilica gel to afford tert-butyl tosyloxycarbamate as a white solid.

To a stirring mixture of 641-3 (200 mg, 0.39 mmol) in CH₂Cl₂ (2 mL) atr.t. were added TsCl (376 mg, 1.96 mmol) and TEA (320 μL, 2.34 mmol).The mixture was stirred at r.t. for 30 mins. The reaction was quenchedwith sat. NaHCO₃ solution. The layers were separated. The aqueous layerwas extracted with EtOAc (2×25 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography of the crude productafforded 641-4 (128 mg) as a colorless oil. LCMS: m/z 681.10 [M+H]⁺.

To a stirring mixture of 641-4 (128 mg, 0.188 mmol) in acetone (2 mL) atr.t. was added LiBr. The mixture was heated at reflux for 1 h and thencooled to r.t. The mixture was concentrated under reduced pressure.Chromatography of residue afforded 641-5 as a colorless oil (80 mg, 72%yield). LCMS: m/z 589 [M+H]⁺.

To a stirring mixture of 641-5 (80 mg, 0.135 mmol) in DCM (1.5 mL) at 0°C. was added DAST (58 μL, 0.41 mmol). The mixture was stirred at 0° C.for 30 mins and then quickly warmed to r.t. for 5 mins. The reaction wasquenched with a cold aq. NaHCO₃ solution. The aqueous layer wasextracted with DCM, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude product mixture was purified via a silicagel column to afford 641-6 (56 mg, 74% yield). LCMS: m/z 591.0 [M+H]⁺.

To a stirring mixture of 641-6 (50 mg, 0.084 mmol) in DMF (1 mL) wereadded tetrabutylammonium azide (240 mg, 0.84 mmol) andtetrabutylammonium iodide (12 mg). The mixture was stirred at 100° C.for several hours. The mixture was directly loaded onto a silica gelcolumn, eluting with hexane:EtOAc to afford 641-7 (30 mg, 64%) as acolorless oil. LCMS: m/z 554.10 [M+H]⁺.

To a stirring mixture of 641-7 (30 mg, 0.054 mmol) in THF:water (10:1,1.1 mL) was added triphenylphosphine, polymer-bound (142 mg, 0.54 mmol).The mixture was stirred at 70° C. for 30 mins and then cooled to r.t.The mixture was filtered through a plug of celite. The plug was washedseveral times with EtOAc. The crude mixture was concentrated underreduced pressure, and the crude product was used in the next stepwithout further purification.

To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid in DMF (1mL) were added HATU (21 mg, 0.054 mmol) and DIPEA (15 μL, 0.11 mmol).The mixture was stirred at r.t. for 5 mins. A solution of 641-8 in DMF(0.5 mL) was added. The mixture was stirred at r.t. for 10 mins. Thereaction was quenched with a 10% aq. solution of NaHCO₃ (10 mL). Themixture was diluted with DCM, and an aqueous work up with DCM wasfollowed. The crude product was purified via prep-HPLC to afford 641-9(20 mg, 52%, 2 steps) as a white solid. LCMS: m/z 718.2 [M+H]⁺.

To a stirring mixture of 641-9 (20 mg, 0.0286 mmol) in AcCN (1 mL) atr.t. were added NaI (22 mg, 0.143 mmol) and TMSCl (19 mg, 0.143 mmol).The mixture was warmed to 60° C. until the starting materials wereconsumed. The mixture was cooled to r.t. and diluted with CH₂Cl₂. Themixture was washed with a 10% aq. solution of Na₂S₂O₃. The aqueous layerwas extracted with DCM (2×10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was furtherpurified via prep-HPLC to afford 641. LCMS: m/z 584.15 [M+H]⁺.

Example 379 Preparation of Compound 573

To a stirring solution of 573-1 (30 mg, 0.41 mmol) in EtOAc:EtOH (5 mL:5mL) was added Pd/C (20 mg). The mixture was placed under a H₂ balloon.The mixture was stirred for several hours until the starting materialwas consumed. The crude mixture was filtered through a plug of celite,and the plug was washed with EtOAc (2×20 mL). The mixture wasconcentrated under reduced pressure, which was used without furtherpurification.

The N-Boc protected amine was dissolved in a 4N HCl in dioxane. Themixture was stirred overnight at r.t. The crude product mixture wasconcentrated under reduced pressure. The crude product mixture waspurified via a prep-HPLC to afford 573 as a white solid. LCMS: m/z590.15 [M+H]⁺.

Example 380 Preparation of Compound 598

To a stirring mixture of 2,6-dichloroisonicotinonitrile (1 g, 5.78 mmol)in Et₂O at r.t. under Ar was added Ti(OiPr)₄ (1.97 mL, 6.65 mmol). Themixture was stirred for 10 mins and then cooled to 0° C. A solution ofEtMgBr (3.54 mL, 12.14 mmol) in 2-methyltetrafuran was added over 10mins. The mixture was stirred at r.t. for 1 h, and then cooled to 0° C.BF₃.OEt (1.3 mL, 10.58 mmol) was added. The mixture was warmed to r.t.and stir for 30 mins. The reaction was quenched with 1N HCl (5 mL) andthen 2N NaOH (10 mL). The mixture was diluted with DCM. The aqueouslayer was extracted with DCM, dried over MgSO4, filtered andconcentrated under reduced pressure. Chromatography of the residueafford 598-1 (100 mg, 8.5%) as a colorless oil. LCMS: m/z 203.1 [M+H]⁺.

To a stirring mixture of 598-1 (100 mg, 0.49 mmol) in DCM (1 mL) at 0°C. were added CBzCl (84.2 mg, 0.49 mmol) and DIPEA (86 μL, 0.49 mmol).The mixture was warmed to r.t. for 20 mins. The reaction was quenchedwith a cold sat. NaHCO₃ solution. The aqueous layer was extracted withDCM, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue afford N—CBz protected amine(100 mg, 60%). LCMS: m/z 337.0 [M+H]⁺.

To a stirring mixture of benzyl(1-(2,6-dichloropyridin-4-yl)cyclopropyl)carbamate (100 mg, 0.297 mmol)in DME (2 mL, deoxygenated prior to using) were added4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(132 mg, 0.59 mmol), a solution of Cs₂CO₃ (290 mg, 0.89 mmol in 0.3 mLof water) and PdCl₂(dppf) (45 mg, 0.062 mmol). The mixture was heatedunder microwave irradiation for 1 h at 110° C. The crude product mixturewas diluted with EtOAc and water. An aqueous workup with EtOAc wasfollowed. The crude product was purified via a silica gel chromatographyto afford desired product. The mixtures was used in the next stepwithout further purification (70 mg). LCMS: m/z 397.10 [M+H]⁺.

To a stirring mixture of products from the previous step (70 mg, 0.176mmol) in DME (1.5 mL, deoxygenated prior to using) were added4-fluorophenylboronic acid (36 mg, 0.259 mmol), a solution of Cs₂CO₃(171 mg, 0.52 mmol in 0.3 mL of water), and PdCl₂(dppf) (26 mg, 0.035mmol). The mixture was carried out under microwave irradiation at 110°C. for 1 h. The crude product was diluted with EtOAc and water. Theaqueous layer was extracted with EtOAc, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel chromatography to yield benzyl(1-(2-(4-fluorophenyl)-6-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-4-yl)cyclopropyl)carbamateas the desired product. LCMS: m/z 457. [M+H]⁺.

To a stirring mixture of 598-2 (50 mg, 0.085 mmol) in t-BuOH:water (3:1,1.3 mL) at r.t. were added potassium osmate dihydrate (8 mg, 0.0215mmol) and tert-butyl tosyloxycarbamate (62 mg, 0.215 mmol). The mixturewas stirred at r.t. overnight, and then diluted with water and DCM. Theaqueous layer was extracted with DCM, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel chromatography to afford 598-3 (24 mg, 37%). LCMS: m/z590.20 [M+H]⁺.

The N-Boc protected amine was dissolved in a solution of HCl in dioxane(2 mL, 4N) at r.t. The mixture was stirred at r.t. until the startingmaterial was consumed. The mixture was concentrated under reducedpressure to afford the crude amino alcohol, which was used withoutfurther purification. LCMS: m/z 490.10 [M+H]⁺.

To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid(9 mg, 0.04 mmol) in DMF (0.5 mL) were added HATU (15.2 mg, 0.04 mmol)and DIPEA (17 μL, 0.1 mmol). The mixture was stirred at r.t. for 10mins. A solution of the crude amino alcohol in DMF (0.2 mL) was added.The mixture was stirred at r.t. for 10 mins. The reaction was quenchedwith a 10% aq. NaHCO₃ solution (1 mL). The mixture was diluted with DCM,and an aqueous work up with DCM was followed. The crude product waspurified via prep-HPLC to afford benzyl(1-(2-(4-fluorophenyl)-6-(1,1,1-trifluoro-2-hydroxy-3-(4-((R)-2-hydroxypropoxy)-3-methoxybenzamido)propan-2-yl)pyridin-4-yl)cyclopropyl)carbamate(7 mg, 24% 2 steps) as a white solid. LCMS: m/z 698.2 [M+H]⁺.

To a stirring mixture of 598-4 (7 mg, 0.01 mmol) in AcCN (0.5 mL) atr.t. were added NaI (7.5 mg, 0.05 mmol) and TMSCl (5.4 mg, 0.05 mmol).The mixture was warmed to 60° C. until the starting material wasconsumed. The mixture was cooled to r.t. and diluted with CH₂Cl₂. Themixture was washed with a 10% aq. Na₂S₂O₃ solution. The aqueous layerwas extracted with DCM (2×10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was furtherpurified via prep-HPLC to afford 598. LCMS: m/z 564.20 [M+H]⁺.

Example 381 Preparation of Compound 600

To a stirring solution of 533 (10 mg, 0.016 mmol) in EtOAc:EtOH (5 mL:1mL) was added Pd/C (15 mg). The mixture was placed under a H₂ balloon.The mixture was stirred for several hours until the starting materialwas consumed. The crude mixture was filtered through a plug of celite,and the plug was washed several times with EtOAc (2×20 mL). The mixturewas concentrated under reduced pressure and purified via prep-HPLC toafford 600 as a white solid (3 mg, 32%). LCMS: m/z 564.2 [M+H]⁺.

Example 382 Preparation of Compound 594

Iodomethane (0.66 mL, 11 mmol) was added dropwise to a solution of2-chloro-3-hydroxy-6-(hydroxymethyl)-4-iodopyridine (2.03 g, 7.1 mmol)and potassium carbonate (2.0 g, 14 mmol) in DMF (8 mL). The mixture wasstirred at r.t. for 1 h. The mixture was diluted with EA, washed withwater and brine, dried and concentrated. The product (1.77 g, 64%)crystallized upon standing.

DIPEA (2.0 mL, 12 mmol) was added dropwise to a solution of(6-chloro-4-iodo-5-methoxypyridin-2-yl)methanol (1.77 g, 5.91 mmol),tert-butylchlorodimethylsilane (1.3 g, 8.9 mmol) and a catalytic amountof imidazole in CH₂Cl₂ (10 mL). The mixture was stirred at r.t.overnight. The mixture was diluted with CH₂Cl₂, washed with 1N HCl andbrine, dried and concentrated. The crude product was purified by columnchromatography (hexane:EA) to yield the product (2.18 g, 75%) as a whitesolid.

Copper cyanide (1.0 g, 12 mmol) was added to a solution of6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-4-iodo-3-methoxypyridine(1.0 g, 2.4 mmol) in dimethyl acetamide (3 mL). The mixture was heatedat 140° C. for 2 h, and then diluted with DCM. A 10% aq. solution ofNH₄OH was added. The mixture was stirred at r.t. for 20 mins, and thelayers were separated. An aqueous work up with EtOAc was followed.Chromatography of residue afforded6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-3-methoxyisonicotinonitrile(520 mg, 70%) as a colorless oil.

To a stirring mixture of6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-3-methoxyisonicotinonitrile(520 mg, 1.66 mmol) in Et₂O (3.9 mL) at 0° C. was added a solution ofMeMgBr in 2-methyltetrafuran (1.47 mL, 4.71 mmol). After 1 h of stirringat r.t., Ti(OiPr)₄ was added. The mixture was heated at reflux for 2 hand then diluted with CH₂Cl₂. The mixture was cooled to r.t., andcopious quantities of Celite were added. The crude mixture was basifiedwith a solution of NaOH (2 mL, 2N) and filtered through a plug ofCelite. The plug was washed several times with DCM. The filtrate waswashed with a 10% aq. HCl solution. The layers were separated, and theorganic layer was washed with sat. NaHCO₃ solution. The aqueous layerwas extracted with EtOAc (2×25 mL). The organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. Chromatographyof residue afforded 594-1 (147 mg, 26%) as a colorless oil. LCMS: m/z345.15 [M+H]⁺.

To a stirring mixture of 594-1 (147 mg, 0.45 mmol) in DCM (1.5 mL) at 0°C. were added CBzCl (114 mg, 0.67 mmol) and DIPEA (233 μL, 0.49 mmol).The mixture was warmed to r.t. for 10 mins. The reaction was quenchedwith a cold sat. NaHCO₃ solution. The aqueous layer was extracted withDCM, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography of the residue afford 594-2 (110 mg, 57%) as awhite solid.

To a stirring mixture of 594-2 (110 mg, 0.25 mmol) in THF (762 μL) at rtwas added dropwise a solution of TBAF (0.85 mL) in THF. The mixture wasstirred at r.t. until the starting material was consumed. Silica gel wasadded, and the mixture was stirred at r.t. for 10 mins. resultingmixture was concentrated under reduced pressure. Chromatography of theresidue 594-3, which was used without further purification. LCMS: m/z365.05 [M+H]⁺.

To a stirring mixture of 594-3 (110 mg, ˜0.3 mmol) in CH₂Cl₂ (1.3 mL) atr.t. was added and Dess-Martin periodinane (383 mg, 0.9 mmol). Themixture was stirred at r.t. until the alcohol was consumed. The reactionwas quenched with a 5% NaHSO₃ solution and a sat. NaHCO₃ solution. Theaqueous layer was extracted with EtOAc (2×25 mL). The organic layerswere dried with Na₂SO₄, filtered and concentrated under reducedpressure. The crude product mixture was purified via a silica gel columnto afford 594-4 (90 mg, 55% 2 steps). LCMS: m/z 363.05 [M+H]⁺.

To a stirring mixture of 594-4 (90 mg, 0.248 mmol) in DMF (0.5 mL) wereadded TMSCF₃ (53 mg, 0.37 mmol) and a TBAF solution in THF (37 μL). Themixture was stirred at r.t. for 1 h. Silica gel was added, and themixture was stirred for 10 mins. The crude mixture was concentratedunder reduced pressure. Chromatography of the residue afford 594-5 (86mg, 80%). LCMS: m/z 433.05 [M+H]⁺.

To a stirring mixture of 594-5 (86 mg, 0.198 mmol) in CH₂Cl₂ (1.0 mL) atr.t. was added the Dess-Martin periodinane reagent (421 mg, 0.99 mmol).The mixture was stirred at r.t. until the alcohol was consumed. Thereaction was quenched with a 5% aqueous solution of NaHSO₃ and a sat.NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2×25 mL).The organic layers were dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product mixture was purified via asilica gel column to afford 594-6 (80 mg, 90%). LCMS: m/z 449.05[M+H₂O+H]⁺.

To a stirring mixture of 594-6 (30 mg, 0.074 mmol) in MeNO₂ (0.5 mL) wasadded TEA (20 μL, 0.147 mmol). The mixture was stirred at r.t. for 30mins, and then diluted with DCM and washed with water. The aqueous layerwas extracted with DCM, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. Chromatography of the residue afford 594-7 (30mg, 82%) as a white solid. LCMS: m/z 492.05 [M+H]⁺.

To a stirring mixture of 594-7 (30 mg, 0.061 mmol) in EtOAc (0.3 mL) atr.t. was added SnCl₂.2H₂O (166 mg, 0.74 mmol). The mixture was heated atreflux for 1 h and then cooled to r.t. The mixture was concentratedunder reduced pressure. The crude product mixture was directly loadedinto a silica gel column to afford 594-8. LCMS: m/z 462.05 [M+H]⁺.

To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid (12.6 mg,0.06 mmol) in DMF (0.5 mL) were added HATU (23 mg, 0.06 mmol) and DIPEA(16 μL, 0.09 mmol). The mixture was stirred at r.t. for 10 mins. Asolution of 594-8 in DMF (0.2 mL) was added, and the mixture was stirredat r.t. for 10 mins. The reaction was quenched with a 10% aq. NaHCO₃solution (10 mL). The mixture was diluted with DCM and an aqueous workup with DCM was followed. The crude product was purified via prep-HPLCto afford benzyl(2-(2-chloro-6-(3-(4-cyclopropoxy-3-methoxybenzamido)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-3-methoxypyridin-4-yl)propan-2-yl)carbamate(30 mg, quantitative) as a white solid. LCMS: m/z 652.15 [M+H]⁺.

To a stirring mixture of benzyl(2-(2-chloro-6-(3-(4-cyclopropoxy-3-methoxybenzamido)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-3-methoxypyridin-4-yl)propan-2-yl)carbamate(30 mg, 0.046 mmol) in DME (2 mL, deoxygenated prior to using) wereadded 4-fluorophenyl boronic acid (8 mg, 0.055 mmol), a solution ofCs₂C03 (45 mg, 0.14 mmol in 0.3 mL of water) and PdCl₂(dppf) (5 mg,0.007 mmol). The mixture was stirred at 110° C. under microwave reactionconditions for 1 h. The crude product mixture was diluted with EtOAc andwater. An aqueous workup with EtOAc was followed. The crude productmixture was purified via a silica gel chromatography to afford theproduct and unreacted starting material (25 mg). LCMS: m/z 712.20[M+H]⁺.

To a stirring solution of N-Cbz protected amine and unreacted startingmaterial from the previous step (25 mg) in EtOAc:i-PrOH:HOAc (5 mL:1mL:1 mL) was added Pd/C (20 mg). The mixture was placed under a H₂balloon. The mixture was stirred for several hours until the startingmaterial was consumed. The crude mixture was filtered through a plug ofcelite, and the plug was washed with EtOAc (2×20 mL). The mixture wasconcentrated under reduced pressure. The crude product mixture waspurified via HPLC to afford 594 as a white solid. LCMS: m/z 578.15[M+H]⁺.

Example 383 Preparation of Compounds 582, 583 and 589

To a stirred solution of 582-1 (50 g, 310 mmol) in anhydrous THF (1.2 L)was added LDA (310 mL, 620 mmol) at −78° C. under N₂. The mixture wasstirred at −78° C. for 0.5 h. A solution of dimethyl carbonate (67.1 g,750 mmol) in dry THF (150 mL) was added dropwise. The solution waswarmed to 0° C. and stirred for 1 h below 0° C. The reaction wasquenched with aq. NH₄Cl (500 mL), extracted with EA (3×1 L). Thecombined organic phase was washed with a. sodium bicarbonate (1 L) andbrine, and dried over sodium sulfate. The organic layer was concentratedto dryness, and the residue was purified by column chromatography(PE:EA=20:1) to give 582-2 (50 g, 73.5%) as a colorless oil.

To a solution of crude 582-2 (50 g, 230 mmol) in dioxane:H₂O (6:1) (1 L)was added 4-fluoro-3-chloro-phenyl boronic acid (40 g, 230 mmol), Cs₂CO₃(223.3 g, 680 mmol) and Pd(dppf)Cl₂ (16.8 g, 23 mmol) under N₂. Themixture was degassed (3×) and refilled with N₂. The mixture was stirredat 80° C. in a pre-heated oil bath for 4 h. After cooling to r.t., themixture was diluted with water (1.5 L) and extracted with EA (3×1 L).The combined organic layers were washed with brine, dried over sodiumsulfate and concentrated in vacuum to dryness. The residue was purifiedby column chromatography (PE:EA=20:1˜15:1) to yield 582-3 (42 g, 58.7%)as a light yellow solid.

To a solution of 582-3 (10 g, 31.9 mmol) in anhydrous THF (100 mL) wasadded LiHMDS (63.9 mL, 63.9 mmol) dropwise at −78° C. The mixture wasstirred at −78° C. for 30 mins. A solution of MeI (9.07 g, 63.9 mmol) indry THF (50 mL) was added dropwise. The mixture was warmed to 0° C. andstirred at 0° C. for 1 h. The reaction was quenched with water (100 mL)and extracted with EA (3×150 mL). The combined organic layers werewashed with brine, dried over sodium sulfate and concentrated in vacuumto dryness. The residue was purified by column chromatography(PE:EA=10:1) to yield 582-4 (3.5 g, 32%) as a light yellow solid.

To a solution of 582-4 (3.2 g, 10.22 mmol) in anhydrous THF (20 mL) wasadded NaHMDS (20.44 mL, 20.44 mmol) dropwise at −78° C. The mixture wasstirred at −78° C. for 30 mins. A solution of BnOCH₂Cl (3.19 g, 20.44mmol) in dry THF (10 mL) was added dropwise. The mixture was warmed to0° C. and stirred for 1 h. The reaction was quenched with water (50 mL)and extracted with EA (3×50 mL). The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuum todryness. The residue was purified by column chromatography (PE:EA=10:1)to yield 582-5 (2.7 g, 59%) as a yellow oil.

To a stirred solution of 582-5 (16.22 g, 36.29 mmol) in anhydrous THF(150 mL) was added LiAlH₄ (1.38 g, 36.29 mmol) powder in portions underN2 at 0° C. for a period of 10-15 mins. The mixture was stirred at 0° C.for 0.5 h. The reaction was quenched with water (100 mL) and filteredvia a plug of celite. The filtrate was extracted with EA (3×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated in vacuum to dryness. The residue was purifiedby column chromatography (PE:EA=3:1) to give 582-6 (13.5 g, 89%) as ayellow oil.

To a stirred solution of 582-6 (5 g, 11.93 mmol) in anhydrous DCM (50mL) was added FeCl₂ (19.4 g, 119.3 mmol) powder in one portion at r.t.The mixture was stirred at r.t. for 1 h. The mixture was diluted withwater (100 mL) and filtered via a bed of celite bed. The filtrate wasextracted with EA (2×150 mL). The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuum todryness. The residue was purified by column chromatography (PE:EA=1:1)to give 582-7 (3.6 g, 92%) as a brown oil.

To a stirred solution of 582-7 (3.5 g, 10.6 mmol) in anhydrous DCM (20mL) was added TEA (5.4 g, 53 mmol) at r.t. MsCl (4.8 g, 42.4 mmol) wasadded dropwise, and the mixture was stirred at r.t. for 1 h. Thesolution was washed with water (20 mL) and brine (20 mL), and thenconcentrated to dryness. The residue was purified by columnchromatography (PE:EA=5:1) to give 582-8 (3.6 g, 69%) as a yellow oil.

582-8 (480 mg, 0.987 mmol) was dissolved in benzyl amine (3 mL). Themixture was heated under microwave irradiation at 135° C. for 5 h. Thecrude mixture was cooled to r.t. and directly loaded into a silica gelcolumn to afford a mixture of products. This mixture was furtherpurified via prep-HPLC to afford 582-9 (100 mg, 25% yield) as acolorless oil; LCMS: m/z 401.05 [M+H]⁺.

To a stirring mixture of 582-9 (100 mg, 0.249 mmol) in DME (2 mL,deoxygenated prior to using) were added4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(111 mg, 0.498 mmol), a solution of Cs₂CO₃ (243 mg, 0.75 mmol in 0.5 mLof water) and PdCl₂(dppf) (36 mg, 0.005 mmol). The mixture was stirredat 110° C. for 2 h under microwave reaction conditions. The crudeproduct mixture was diluted with EtOAc and water. An aqueous workup withEtOAc was followed. The crude product mixture was purified via a silicagel chromatography to afford 582-10 (114 mg, quantitative yield). LCMS:m/z 461.05 [M+H]⁺.

To a stirring mixture of 582-10 (26 mg, 0.056 mmol) in t-BuOH:water(3:1, 1.3 mL total volume) at r.t. were added potassium osmate dihydrate(3 mg, 0.008 mmol) and tert-butyl tosyloxycarbamate (32 mg, 0.112 mmol).The mixture was stirred at r.t. overnight. The mixture was diluted withwater and diluted with DCM. The aqueous layer was extracted with DCM,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product mixture was purified via a silica gel chromatography toafford 582-11 (15 mg, 45%). LCMS: m/z 594.2 [M+H]⁺.

The N-Boc protected amine was dissolved in HCl in dioxane (3 mL, 4N).The mixture was stirred at r.t. for several hours until the startingmaterial was consumed. The crude product was concentrated under reducedpressure and directly used in the next step without furtherpurification. Coupling of the crude amine with4-cyclopropoxy-3-methoxybenzoic acid following the general procedure for598 afforded 589 as a white solid. LCMS: m/z 684.20 [M+H]⁺.

To a stirring solution of 589 (38 mg, 0.064 mmol) in EtOAc:iPrOH:HOAc (5mL:1 mL:1 mL) was added a 10% Pd/C (40 mg). The mixture was placed undera H₂ balloon. The mixture was stirred for several hours until thestarting material was consumed. The crude mixture was filtered through aplug of celite, and the plug was washed with EtOAc (2×20 mL). Themixture was concentrated under reduced pressure and purified viaprep-HPLC to afford 583 and 582. 583: LCMS: m/z 560.15 [M+H]⁺ and 582:LCMS: m/z 594.15 [M+H]⁺.

Example 384 Preparation of Compound 590

Compound 590 was prepared following the general procedure for 583 using(R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid and HATU. LCMS: m/z578.15 [M+H]⁺.

Example 385 Preparation of Compound 584

584-1 was prepared following the general procedure for 583 using3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid and HATU.

To a stirring mixture of 584-1 in DCM (1 mL) was added TFA (0.2 mL). Themixture was stirred at r.t. for 5 mins, and then diluted with DCM. Thereaction quenched with a cold NaHCO₃ solution. The aqueous layer wasextracted with DCM, dried with Na₂SO₄, filtered and concentrated underreduced pressure. The crude product mixture was purified via prep-HPLCto afford 584 as a white solid. LCMS: m/z 606.25 [M+H]⁺.

Example 386 Preparation of Compound 588

To a stirring mixture of2-(2-chloro-6-(3-chloro-4-fluorophenyl)pyridin-4-yl)propan-2-amine (200mg, 0.67 mmol) in DCE (1 mL) at r.t. were added acetone (78 mg, 1.33mmol), HOAc (10 mg) and Na(OAc)₃BH (280 mg). The mixture was stirred atr.t. overnight. The mixture was diluted with DCM, and the reactionquenched with a cold NaHCO₃ solution. The aqueous layer was extractedwith DCM, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The crude product mixture was purified via a silica gel columnto afford 588-1 (180 mg, 79%) as a colorless oil. LCMS: m/z 341.0[M+H]⁺.

Compound 588 was prepared following the general procedure for 582 and583. LCMS: m/z 607.2 [M+H]⁺.

Example 387 Preparation of Compound 597

To a stirring mixture of 4-(3-hydroxycyclobutoxy)-3-methoxybenzoic acid(70 mg, 0.168 mmol) in DMF (1 mL) were added HATU (64 mg, 0.168 mmol)and DIPEA (60 μL, 0.336 mmol). The mixture was stirred at r.t. for 5mins. A solution of 597-1 in DMF (0.5 mL) was added, and the mixture wasstirred at r.t. for 10 mins. The reaction was quenched with a 10% aq.solution of NaHCO₃ (1 mL). The mixture was diluted with DCM, and anaqueous work up with DCM was followed. The crude product was purifiedvia prep-HPLC to afford 597-2 (80 mg, 75%) as a white solid. LCMS: m/z636.15 [M+H]⁺.

To a stirring mixture of 597-2 (40 mg, 0.063 mmol) in DME:EtOH:H₂O (1.5mL:0.5 mL:0.2 mL, deoxygenated prior to using) were added4-fluorophenylboronic acid (9 mg, 0.063 mmol), K₃PO₄. 7H₂O (64 mg, 0.19mmol), KH₂PO₄ (25 mg, 0.16 mmol) and PdCl₂(dppf) (7.5 mg, 0.01 mmol).The mixture was carried out under microwave irradiation at 110° C. for 5h. The crude product mixture was diluted with EtOAc and water. Anaqueous workup with EtOAc was followed. The crude product mixture waspurified via a silica gel chromatography to afford 597-3. LCMS: m/z696.20 [M+H]⁺.

To a stirring mixture of 597-3 in MeOH (5 mL) at r.t. was added asolution of HCl in dioxane (4N, 1 mL). The mixture was stirred for 10mins, and then concentrated under reduced pressure. The crude productwas purified via HPLC to afford 597 (30 mg, 70%) as a white solid. LCMS:m/z 592.1 [M+H]⁺.

Example 388 Preparation of Compound 574

To a stirring mixture of 574-1 (130 mg, 0.21 mmol) in THF (2 mL) at r.t.was added dropwise a solution of MeMgBr in toluene (0.91 mL, 1.27 mmol).The mixture was stirred at r.t. for 2 h, and then diluted with EtOAc.The reaction quenched with a sat. NH₄Cl solution. The layers wereseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel chromatography to afford a mixture that included 574-2.LCMS: m/z 628.20 [M+H]⁺.

574-2 (40 mg) was hydrogenated over 10% Pd/C (35 mg) in EtOAc:EtOH (5 mLeach) for 2 h. The catalyst was removed by filtration, and the crudeproduct was used in the next step without further purification. LCMS:m/z 594.25 [M+H]⁺.

To HCl in dioxane (5 mL, 4N) was added 574-3 (20 mg), and the mixturewas stirred at r.t. for 3 h. The mixture was concentrated, and the crudeproduct was purified by prep-HPLC to provide 574. LCMS: m/z 494.20[M+H]⁺.

Example 389 Preparation of Compound 572

To a stirring mixture of 572-1 (25 mg, 0.0357 mmol) in pyridine (1 mL)was added a solution of isopropylchloroformate (110 μL, 0.101 mmol) intoluene. The mixture was stirred at r.t. for 2 h. The mixture wasdiluted with DCM, and the reaction quenched with a sat. NaHCO₃ solution.The layers were separated, and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a silica gel chromatography to afford 572-2 asa colorless oil. LCMS: m/z 786.25 [M+H]⁺.

To a stirring mixture of 572-2 (22 mg, 0.032 mmol) in AcCN (1 mL) at 0°C. were added NaI (24 mg, 0.15 mmol) and TMSCl (25 μL, 0.15 mmol). Themixture was stirred for an 10 mins, and then warmed to r.t. The mixturewas diluted with EtOAc and washed with a 10% aq. Na₂S₂O₃ solution. Theorganic layer were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The mixture was concentrated, andthe crude product purified by prep-HPLC to provide 572. LCMS: m/z 686.2[M+H]⁺.

Example 390 Preparation of Compound 591

To a stirring mixture of 544 (50 mg, 0.075 mmol) in HOAc:EtOAc (6 mL,5:1) was added Pd/C (30 mg). The mixture was placed under a H₂ balloonfor several hours. The mixture was filtered through a plug of Celite,and the plug was washed several times with EtOAc. The filtrate wasconcentrated under reduced pressure and purified via prep-HPLC to afford544. LCMS: m/z 582.10 [M+H]⁺.

Example 391 Preparation of Compound 640

Suzuki coupling of 640-1 (50 mg) with 4-chlorophenylboronic acidfollowed by sulfinamide hydrolysis afforded 640 (20 mg) as a whitesolid. LCMS: m/z 582.15 [M+H]⁺.

Example 392 Preparation of Compound 646

Compound 646 (white solid, 11.6 mg) was prepared following the generalprocedure for 640 using 646-1 (25 mg). LCMS: m/z 596.10 [M+H]⁺.

Example 393 Preparation of Compound 666

Compound 666 (white solid, 6.7 mg) was prepared following the generalprocedure for 640 using 646-1 (20 mg) and 4-chloro-3-fluorophenylboronic acid. LCMS: m/z 614.15 [M+H]⁺.

Example 394 Preparation of Compound 649

Compound 649 (white solid, 19.6 mg) was prepared following the generalprocedure for 640 using 640-1 (40 mg) and(6-oxo-1,6-dihydropyridin-3-yl)boronic acid. LCMS: m/z 565.15 [M+H]⁺.

Example 395 Preparation of Compound 665

Compound 649 (white solid, 9.2 mg) was prepared following the generalprocedure for 640 using 646-1 (35 mg) and(4-fluoro-3-(trifluoromethyl)phenyl)boronic acid. LCMS: m/z 648.15[M+H]⁺.

Example 396 Preparation of Compound 628

To a stirring mixture of methyl-4-methoxybenzoate (1 g, 5.49 mmol) inDMF (5 mL) at r.t. was added K₂CO₃ (1.14 g, 8.24 mmol) and2-bromoacetonitrile (653 mg, 5.49 mmol). The mixture was stirred at r.t.for 3 h, and then diluted with EtOAc and water. The aqueous layer wasextracted with EtOAc. The organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified via a silica gel chromatography to afford 628-1 as a whitesolid.

To a stirring mixture of 628-1 (600 mg, 2.72 mmol) in THF (6 mL) wasadded dropwise a solution of borane and DMS complex in THF (0.26 mL,2.72 mmol) at r.t. The mixture was slowly warmed to 60° C. for 1 h. Themixture was cooled to r.t. and diluted with EtOAc. The reaction wasquenched with an aq. solution of HCl (1N). The mixture was stirred atr.t. for 10 mins and then neutralized with a sat. NaHCO₃ solution. Thelayers were separated, and the aqeuous layer was extracted with EtOAc.The organic layers were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified via a silica gelchromatography to afford 628-2 as a white solid. LCMS: m/z 226.1 [M+H]⁺.

To a stirring mixture of 628-2 (40 mg, 0.177 mmol) in DCM (0.6 mL) at 0°C. were added diphosgene (32 mg, 0.177 mmol) and DIPEA (42 μL, 0.27mmol). The mixture was warmed to r.t. for 20 mins and then concentratedunder reduced pressure. The crude product was dissolved in toluene (0.5mL), and azidotrimethylsilane (0.14 mL) and 1 drop of BF₃. OEt₂ wereadded. The mixture was heated at reflux for 1 h. The crude mixture wascooled to r.t. and diluted with DCM. The reaction was quenched withwater, and extracted with DCM. The organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a silica gel chromatography to afford 628-3 asa white solid (18 mg, 36% in 2 steps).

628-3 was dissolved in a solution of HCl in dioxane (1 mL). An aqueoussolution of HCl (6N, 1 mL) was added, and the mixture was heated at 80°C. overnight. The mixture was cooled to r.t. and diluted with EtOAc. Theaqueous layer was extracted with EtOAc. The organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via prep-HPLC to afford 628-4 as a white solid.LCMS: m/z 302.85 [M+Na]⁺.

To a stirring mixture of tert-butyl(2-(2-(3-amino-1,1,1-trifluoro-2-hydroxypropan-2-yl)-6-(3-chloro-4-fluorophenyl)pyridin-4-yl)propan-2-yl)carbamate(8 mg, 0.0163 mmol) and 628-4 (from the previous step) in DCM (0.3 mL)were added EDCI (6.2 mg, 0.032 mmol), HOAt (4.5 mg, 0.033 mmol) and TEA(20 μL). The mixture was stirred for 5 mins, and the reaction wasquenched with 2 drops of a solution of HCl (1N). The organic layer wastransferred to a different flask and concentrated under reducedpressure. The crude product was purified via prep-HPLC to afford thedesired product as a white solid; LCMS: m/z 754.20 [M+H]⁺.

628-5 was dissolved in a solution of HCl in dioxane (5 mL, 4N). Themixture was stirred at r.t. until the starting material was consumed.The crude mixture was concentrated under reduced pressure and purifiedvia prep-HPLC to afford 628 as a white solid (8.5 mg). LCMS: m/z 654.1[M+H]⁺.

Example 397 Preparation of Compound 636

To a stirring mixture of 636-1 (130 mg, 0.192 mmol) in DMF (1 mL) wereadded K₂CO₃ (80 mg, 0.576 mmol) and 2-bromoacetonitrile (46 mg, 0.38mmol). The mixture was stirred at r.t. until the starting material wasconsumed. The mixture was diluted with EtOAc and washed with brine. Theaqueous layer was extracted with EtOAc, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel column to afford 636-2 as a colorless oil (40 mg). LCMS:m/z 715.15 [M+H]⁺.

To a stirring mixture of 636-2 (20 mg, 0.028 mmol) in pyridine (0.3 mL)was added NH₂OH.HCl (10 mg). The mixture was stirred at reflux forseveral hours. The mixture was cooled to r.t., diluted with toluene andconcentrated under reduced pressure. This process was repeated twice.The crude product was purified via a silica gel column to afford 636-3as a colorless oil (10 mg).

To a stirring mixture of 636-3 (10 mg, 0.013 mmol) in EtOAc:HOAc:EtOH(5:1:1, 7 mL) was added Pd/C (20 mg). The mixture was placed under a H₂balloon for several hours. The mixture was filtered through a plug ofCelite, and the plug was washed several times with EtOAc. The filtratewas concentrated under reduced pressure and purified via prep-HPLC toafford 636 (4.0 mg) as a white solid. LCMS: m/z 580.15 [M+H]⁺.

Example 398 Preparation of Compound 652

To a stirring mixture of 652-1 (750 mg, 2.12 mmol) were added1-chlorohex-5-en-2-one (390 mg, 2.33 mmol) and potassium carbonate (410mg, 2.97 mmol) in acetone (4.0 mL). The mixture was stirred at 50° C.for 2 h. The volatiles were removed under reduced pressure, and theresidue was partitioned between water and EtOAc. The layers wereseparated, and the organic layers were dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel column to afford 652-2 as a white solid (480 mg, 50%).LCMS: m/z 449.90 [M+H]⁺.

A mixture of 652-2 (420 mg, 1.18 mmol), 2-methylpropane-2-sulfamide (157mg, 1.31 mmol) and titanium(IV) ethoxide (770 μL, 2.6 mmol) in THF (7mL) was heated to 70° C. (sealed vial, degassed and purged with N₂). Themixture was stirred 70° C. for 3 h. The mixture was diluted with EtOAcand water was added. The mixture was stirred for 5 mins and thenfiltered through a pad of celite. The layers were separated, and theaqueous layer was extracted with EtOAc. The combined organic layers weredried with Na₂SO₄ and filtered. The volatiles were removed under reducedpressure. Crude 652-3 was used in the next step without furtherpurification. LCMS: m/z 552.95 [M+H]⁺.

n-Buthyllithium (2.5 M solution in hexane, 0.64 mL, 1.6 mmol) was addedto a solution of ethylmagnesium bromide (3.42 M in 2-Me THF, 0.24 mL,0.8 mmol) in THF (2.5 mL), which had been pre-cooled to 0° C. After 10mins, the mixture was cooled to −78° C. A solution of 652-3 (460 mg,0.83 mmol) in THF (1 mL) was added dropwise, and the mixture was stirredat −78° C. for 15 mins. The reaction was quenched with MeOH and dilutedwith EtOAc. The organic layer was washed with brine, and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure.Chromatography of the residue afforded 652-4 as a brownish oil. LCMS:m/z 427.05 [M+H]⁺.

To a stirring mixture of 652-4 (180 mg, 0.42 mmol) in DCM (2 mL) wasadded Dess-Martin reagent (537 mg, 1.26 mmol). The mixture was stirredat r.t. until the starting material was consumed. The mixture wasdiluted with EtOAc. The reaction quenched with 5% of NaHSO₃ and a sat.NaHCO₃ solution. The layers were separated, and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a silica gel column to afford 652-5 as a whitesolid. LCMS: m/z 443.1 [M+H+H₂O]⁺.

To a stirring mixture of 652-5 (135 mg, 0.305 mmol) in nitromethane (0.5mL) at r.t. was added TEA (63 μL, 0.46 mmol). The mixture was stirred atr.t. for 30 mins and then diluted with DCM. The reaction was quenchedwith a sat. NaHCO₃ solution. The layers were separated, and the aqueouslayer was extracted with DCM. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a silica gel column to afford 652-6 as a whitesolid (140 mg, 94%). LCMS: m/z 486.05 [M+H]⁺.

To a stirring mixture of 652-6 (50 mg, 0.1 mmol) in EtOH:water (10:1,1.1 mL) was added Fe (28 mg, 0.5 mmol) and NH₄Cl (27 mg, 0.5 mmol). Themixture was heated at 80° C. for 30 mins and then cooled to r.t. Themixture was diluted with DCM (5 mL), and the reaction was quenched witha solution of NaOH (2N, 1 mL). The layers were separated, and theaqueous layer was extracted with DCM (2×5 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified via a silica gel column toafford 652-7 as a white solid. LCMS: m/z 456.1 [M+H]⁺.

To a stirring mixture of3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (14.5 mg, 0.044mmol) in DMF (0.2 mL) were added HATU (17 mg, 0.044 mmol) and DIPEA (17μL, 0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solutionof 652-7 (20 mg, 0.044 mmol) in DMF (0.1 mL) was added, and the mixturewas stirred at for 10 mins. The reaction was quenched with a 10% aq.solution of NaHCO₃ (1 mL). The mixture was diluted with DCM, and anaqueous work up with DCM was followed. The crude product was purifiedvia prep-HPLC to afford 652-8 (6.5 mg, 19%) as a white solid. LCMS: m/z770.25 [M+H]⁺.

To a stirring mixture of 652-8 (6.5 mg, 0.008 mmol) in DME:EtOH:H₂O (1.0mL:0.3 mL:0.1 mL, deoxygenated prior to using) were added4-fluorophenylboronic acid (9 mg, 0.063 mmol), K₃PO₄.7H₂O (14.3 mg, 0.04mmol), KH₂PO₄ (5.5 mg, 0.04 mmol) and PdCl₂(dppf) (6.0 mg, 0.008 mmol).The mixture was carried out under microwave irradiation at 110° C. for 5h. The crude product was concentrated under reduced pressure andpurified via a silica gel chromatography to afford 652-9. LCMS: m/z830.2 [M+H]⁺.

To a stirring mixture of 652-9 in t-BuOH:H₂O (3:1, 0.4 mL) were addedK₂OsO₄*2H₂O (1 mg). The mixture was stirred for 2 h and NaIO₄ (5 mg) wasadded. The mixture was stirred at r.t. overnight. The mixture was loadeddirectly into a silica gel column to afford 652-10. LCMS: m/z 832.3[M+H]⁺.

To a stirring mixture of 652-10 in MeOH (1.0 mL) was added a solution ofHCl in dioxane (0.2 mL). The mixture was stirred for 10 mins at r.t. andconcentrated under reduced pressure. Crude 652-11 was used in the nextstep without further purification.

652-11 was dissolved in MeOH (0.5 mL) was added NaBH₄ (1.6 mg). Themixture was stirred at r.t. for 10 mins and then diluted with EtOAc. Thereaction was quenched with a sat. NaHCO₃ solution. The layers wereseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. Crude 652-12 was used in the next step without furtherpurification.

To a stirring mixture of 652-12 in DCM (1.0 mL) was added TFA (0.1 mL).The mixture was stirred at r.t. until the starting material wasconsumed. The mixture was diluted with DCM, and the reaction wasquenched with a cold sat. NaHCO₃ solution. The layers were separated,and the aqueous layer was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified via prep-HPLC to afford 652 asa white solid (1.0 mg). LCMS: m/z 592.20 [M+H]⁺.

Example 399 Preparation of Compound 645

645-2 was prepared following the general procedure for 635-2. LCMS: m/z610.10 [M+H]⁺. 645-3 was prepared following the general procedure for635-3. LCMS: m/z 720.20 [M+H]⁺. Compound 645 (15.7 mg) was preparedfollowing the general procedure for 635 using 645-3 (45 mg, 0.063 mmol).LCMS: m/z 616.15 [M+H]⁺.

Example 400 Preparation of Compound 662

Compound 662 (5.7 mg) was prepared following the general procedure for645. LCMS: m/z 616.10 [M+H]⁺.

Example 401 Preparation of Compound 663

Compound 663 (11.4 mg) was prepared following the general procedure for645. LCMS: m/z 584.15 [M+H]⁺.

Example 402 Preparation of Compound 647

647-3 was prepared following the general procedure for 635-3. LCMS: m/z839.25 [M+H]⁺. 647-4 was prepared following the general procedure for635. 647-4 (51 mg, 0.084 mmol) was treated with TBAF (1M in THF, 0.1 mL,0.1 mol) in THF (2 mL) at 70° C. for 2 h. The mixture was concentrated,and the crude product purified by silica gel chromatography(CH₂Cl₂:MeOH:NH₃) to provide 647 (10 mg, 19%). LCMS: m/z 605.15 [M+H]⁺.

Example 403 Preparation of Compound 648

648-2 was prepared following the general procedure for 637-4. LCMS: m/z629.05 [M+H]⁺. 648-3 was prepared following the general procedure for635-3. LCMS: m/z 719.15 [M+H]⁺. Compound 648 (13.5 mg) was preparedfollowing the general procedure for 635 using 648-3 (27 mg, 0.038 mmol).LCMS: m/z 615.15 [M+H]⁺.

Example 404 Preparation of Compound 651

651-2 was prepared following the general procedure for 637-2. LCMS: m/z730.20 [M+H]⁺. 651-3 was prepared following the general procedure for637-3. LCMS: m/z 787.30 [M+H]⁺.

A solution of 651-3 (15 mg, 0.019 mmol) in CH₃CN (0.5 mL) was addeddropwise to a solution of isopentyl nitrite (4 uL, 0.029 mmol) andcopper bromide (3 mg, 0.023 mmol) in CH₃CN (1 mL) at 65° C. The mixturewas stirred at 65° C. for 1 h and then cooled to 0° C. The reaction wasquenched with the addition of 1N HCl. The aqueous layer was basifiedwith sodium bicarbonate and extracted with EA. The product was usedwithout further purification to provide 651-4. LCMS: m/z 748.15 [M+H]⁺.

Trifluoroacetic acid (0.1 mL) was added to a solution of 651-4 in CH₂Cl₂(0.9 mL), and the reaction was stirred at r.t. for 5 mins. The mixturewas cooled to 0° C. The reaction was quenched with bicarbonate andextracted with EA. The product was purified by reverse-phase HPLC toyield 651 (4.0 mg). LCMS: m/z 628.05 [M+H]⁺.

Example 405 Preparation of Compound 661

Compound 661 was prepared following the general procedure for 651. LCMS:m/z 563.15 [M+H]⁺.

Example 406 Preparation of Compound 493

Compound 493 was prepared following the general procedure for 397 using(S)-3-methoxy-4-((2-oxopyrrolidin-3-yl)oxy)benzoic acid. LCMS: m/z640.15 [M+H]⁺.

Example 407 Preparation of Compound 587

To a stirring mixture of 587-1 (200 mg, 0.67 mmol) in DCE (1 mL) at r.t.were added acetone (78 mg, 1.33 mmol), HOAc (10 mg), and Na(OAc)₃BH (280mg). The mixture was stirred at r.t. overnight. The mixture was dilutedwith DCM, and the reaction was quenched with a cold NaHCO₃ solution. Theaqueous layer was extracted with DCM, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified viaa silica gel column to afford 587-1 (180 mg, 79%) as a colorless oil.LCMS: m/z 341.0 [M+H]⁺.

Compound 587 (35 mg) was prepared in 4 steps from 587-2 (180 mg). LCMS:m/z 641.15 [M+H]⁺.

Example 408 Preparation of Compound 664

Compound 664 is a single diastereomer of 626 and was obtained by chiralseparation of 626 via SFC system. +ESI-MS: m/z 570.15 [M+H]⁺.

Example 409 Preparation of Compound 642

To a stirring mixture of 642-1 (540 mg, 1.76 mmol) in DMF (5 mL,deoxygenated prior to use) were added Pd(OAc)₂ (119 mg, 0.17 mmol), PPh₃(102 mg, 0.387 mmol), TEA (0.3 mL, 2.11 mmol) and ethyl acrylate (0.42mL, 3.87 mmol). The mixture was stirred at 85° C. overnight. The mixturewas diluted with EtOAc and washed with brine. The layers were separated,and the aqueous layer was extracted with EtOAc. The organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified via a silica gel chromatography to afford642-2 as a yellow solid (410 mg, 83%). LCMS: m/z 280.05 [M+H]⁺.

To a stirring mixture of 642-2 in a solution of HCl in dioxane (3 mL)was added concentrated HCl (1 mL). The mixture was stirred at 90° C.overnight. The crude product was cooled to r.t. and concentrated underreduced pressure to afford 642-3 as a brown solid. The solid wasdissolved in toluene and concentrated under reduced pressure (2×). Crude642-3 was used in the next step without further purification. LCMS: m/z220.0 [M+H]⁺.

To a stirring mixture of 642-3 (63 mg, 0.144 mmol) in DMF (0.5 mL) wereadded EDCI (33 mg, 0.173 mmol), HOAt (23 mg, 0.173 mmol) and TEA (41 μL,0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solution of642-4 (60 mg, 0.144 mmol) in DMF (0.5 mL) was added. The mixture wasstirred r.t. for 10 mins. The reaction was quenched with a 10% aq.solution of NaHCO₃ (1 mL). The mixture was diluted with DCM, and anaqueous work up with DCM was followed. The crude product was purifiedvia prep-HPLC to afford 642-5 (20 mg) as a white solid. LCMS: m/z 617.1[M+H]⁺.

To a stirring mixture of 642-5 (20 mg, 0.032 mmol) in DME:EtOH:H₂O (1.0mL:0.3 mL:0.1 mL, deoxygenated prior to using) were added4-fluorophenylboronic acid (9 mg, 0.063 mmol), K₃PO₄. 7H₂O (43 mg, 0.128mmol), KH₂PO₄ (17.4 mg, 0.128 mmol) and PdCl₂(dppf) (20 mg). The mixturewas carried out under microwave irradiation at 110° C. for 5 h. Thecrude product was concentrated under reduced pressure, and then purifiedvia a silica gel chromatography to afford 642-6 as a brownish oil. LCMS:m/z 677.15 [M+H]⁺.

To a stirring mixture of 642-6 in MeOH (1 mL) at r.t. was added asolution of HCl in dioxane (0.2 mL, 4N). The mixture was stirred at r.t.for 5 mins and then concentrated under reduced pressure. The crudeproduct was purified via prep-HPLC to afford 642 (8.5 mg) as a whitesolid. LCMS: m/z 573.1 [M+H]⁺.

Example 410 Preparation of Compound 476

Diisopropylazadicarboxylate (0.29 mL, 1.5 mmol) was added to a solutionof methyl 3-fluoro-4-hydroxybenzoate (0.21 g, 1.2 mmol, ethyl glycolmono-tert-butyl ether (0.32 mL, 2.5 mmol) and polymer boundtriphenylphosphine (1.1 g, 1.9 mmol) in THF (5 mL). The mixture wasstirred at r.t. for 1 h. The resin was removed by filtration, and themixture was concentrated. The product was purified by columnchromatography (hexane:EA) to 476-1 (0.34 g, 98%).

NaOH (2N, 3 mL) was added to a solution of 476-1 (0.34 g, 1.2 mmol) inMeOH (10 mL), and the mixture was heated at reflux for 1.5 h. Themixture was acidified with 1N HCl and extracted with EA. The organicextracts were washed with brine, dried and concentrated to obtain 476-2(0.29 g, 91%).

476-3 was prepared following the general procedure for 635-2 using476-2. 476-4 was prepared following the general procedure for 635-3using 476-3.

HCl (4N in dioxane, 1 mL) was added to a solution of 476-4 (32 mg, 0.049mmol) in CH₂Cl₂ (1 mL), and the mixture was stirred at r.t. for 5 h. Themixture was concentrated and the crude product purified by HPLC to yield476. LCMS: m/z 555.05 [M+H]⁺.

Example 411 Preparation of Compound 481

Compound 481 (8.7 mg) was prepared following the general procedure for645. LCMS: m/z 562.15 [M+H]⁺.

Example 412

The following compounds were prepared following one or more of themethods provided herein.

No. Structure MS 472

nd 484

568.0 [M + H]⁺ 492

567.0 [M + H]⁺ 668

579.2 [M + H]⁺ 669

610.1 [M + Na]⁺ 670

563 [M + H]⁺ 671

563.0 [M + H]⁺ 672

578.0 [M + H]⁺ 673

617.1 [M + H]⁺ 674

591.1 [M + H]⁺ 675

614.0 [M + Na]⁺ 676

570.1 [M + H]⁺ 677

nd 678

nd 679

nd 680

nd 681

nd 682

nd

Example A RSV Antiviral Assay

CPE reduction assays are performed as described by Sidwell and Huffmanet al., Appl. Microbiol. (1971) 22(5):797-801 with slight modifications.HEp-2 cells (ATCC #, CCL-23) are seeded at a density of 1,500 cells/30μl/well into the 384-well cell plate(s) (Corning #3701) one day prior tothe assay. Compounds are added into 384-well cell plates by Labcyte POD810 Plate Assembler system. Each of the test compounds is provided toduplicate wells of a 384-well cell plate at final concentrationsstarting from 100 μM or 1 μM using 1/3 stepwise dilutions for 9 points.Quick-thaw Respiratory Syncytial Virus (RSV) long strain (ATCC #VR-26)stock in a 37° C. water bath. Place on ice until ready to use. Virusesare diluted to the concentration of 100 TCID₅₀/30 μL with medium and 30μl diluted RSV are added into related wells of 384-well cell plates. Foreach plate, sixteen wells are set aside as uninfected, untreated cellcontrols (CC), and nine wells per test plate receive virus only as acontrol for virus replication (VC). The final DMSO concentration of allwells is 1%. Place the plates at 37° C., 5% CO₂ for 5 days.

After 5 days incubation, observe the CPE of cells in all wells. Cellcontrols should be natural and have no cell fusion; Cells in the viruscontrol wells should exhibit signs of virus cytopathology (giant cellformation, syncytia). Six pi of cell counting kit-8 reagent (CCK-8,Dojindo Molecular Technologies Inc., CK04-20) are added to each well,which allows colorimetric assays to determine the number of viable cellsthrough the dehydrogenase activity detection. After 3-4 hour incubation,the absorbance of each well is measured with a spectrophotometric platereader at 450 nm wavelength, using a 630 nm filter as backgroundaccording to manufacturer's instruction. The 50% effective concentration(EC₅₀) is calculated by using regression analysis, based on the meanO.D. at each concentration of compound.

Compounds of Formula (I) are active in the assay against the RSV virusas demonstrated in Tables A and B. Table A includes compounds with anEC₅₀ value that is less than 1 μM. Table B includes compounds with anEC₅₀ value that is equal to or higher than 1 μM and less than 50 μM.Other tested compounds disclosed herein had an EC₅₀ value of 50 μM orgreater.

TABLE A Compound 101 115 116 116b 117 117b 118 118b 119 120 120b 122122a 123 124 125 126 127 130 135 140 142 143 166 167 176 181 182 184 185189 191 192 193 194 195 198 199 200 202 204 205 208 209 210 211 212 213214 217 218 219 220 221 222 223 224 226 227 228 232 234 235 237 238 239240 241 243 244 245 246 248 249 250 255 256 257 258 259 260 261 262 263267 270 272 273 274 281 282 283 284 285 287 289 292 294 296 297 298 299303 304 305 308 309 310 312 314 315 317 318 320 321 322 323 324 325 326327 328 330 331 333 334 335 336 338 339 340 342 343 344 345 346 347 348349 353 356 357 358 359 360 361 362 364 365 366 368 369 370 371 372 373383 384 385 387 388 391 392 394 396 400 403 405 406 409 411 413 414 415418 419 421 423 424 425 426 428 429 431 433 434 435 436 442 443 444 445447 448 449 451 452 453 454 455 456 459 460 461 462 464 465 466 467 469470 473 474 475 476 479 482 483 485 486 487 488 489 490 491 494 495 496497 498 498d 499 500 501 502 503 504 505 507 508 510 514 515 516 517 518519 520 521 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539540 541 542 543 545 546 547 548 550 551 552 553 554 556 557 558 559 560562 563 565 568 569 570 571 574 575 577 579 580 583 586 587 590 591 592593 594 595 596 597 598 599 604d 605a 605b 605d 610 611 612 614 615 619620 621 623b 624b 626 627 628 629 630 631 632 633b 634 635 638 640 642643 644 645 646 650 653 654 656 662 663 664 665 666 667

TABLE B Compound 100 102 104 106 107 108 109 111 112 113 114 116a 117a118a 120a 121 122b 129 131 132 133 134 137 145 148 149 150 161 165 174175 177 178 179 196 206 207 215 216 229 233 251 252 253 254 264 265 266275 283 186 187 190 197 236 268 276 277 278 279 280 286 290 302 313 337368 404 407 410 416 417 432 437 438 440 450 463 471 477 478 484 492 549561 604b 604a 605c 607 608 609 623a 624a 633a 637 639 655 673

Example B Cytotoxicity Determination

In order to determine the compound cytotoxicity, in parallel, each ofthe compounds is applied to duplicate wells in a 384-well cell plate atserial final concentrations starting from 100 μM using 1/2 stepwisedilutions for 7 points without addition of virus. Incubate the cells at37° C., 5% CO₂ for 5 days. Add 6 μL CCK-8 into each well and incubate ina CO₂ incubator at 37° C. for 3-4 hours. Read the plates to obtain theoptical densities which are used to calculate 50% cytotoxicityconcentration (CC₅₀).

Compounds of Formula (I) are not cytotoxic as shown in Tables C and D.Table C includes compounds with a CC₅₀ value that is greater than 100μM. Table D includes compounds with a CC₅₀ value that is equal to orless than 100 μM and greater than 10 μM. Other tested compoundsdisclosed herein had a CC₅₀ value of less than 10 μM.

TABLE C Compound 108 109 116a 117b 120 120b 121 123 135 150 175 176 177178 179 180 181 182 183 187 189 190 191 192 194 195 196 199 205 206 209213 220 228 229 233 234 236 244 245 247 248 287 291 292 294 302 303 304331 335 345 353 358 370 373 387 403 404 405 406 408 419 420 421 427 439441 446 447 451 470 474 484 492 561 562 580 604a 604b 608 611 612 613615 616 620 621 623a 623b 624a 624b 625 627 628 634 643 653 655 670 671672 673 674 675

TABLE D Compound 100 101 102 104 106 107 110 111 112 113 114 115 116116b 117 117a 118 118a 118b 119 120a 122 122a 122b 124 125 126 127 129130 131 132 133 134 137 140 142 143 145 148 149 161 163 165 166 167 174184 185 186 193 197 200 202 204 207 208 210 211 212 214 215 216 217 218219 221 222 223 224 226 227 232 235 237 238 239 240 241 242 243 246 249250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267268 269 270 277 278 279 283 285 286 288 289 290 293 295 296 297 298 299305 308 309 310 312 313 315 317 318 320 321 322 326 327 328 330 333 334336 337 338 339 340 342 343 344 346 347 348 349 356 357 359 360 361 362364 365 366 368 369 371 372 383 384 385 386 388 391 392 396 400 407 409410 411 412 413 414 415 416 417 418 422 423 424 425 426 428 429 430 431432 433 434 435 436 437 438 440 442 443 444 445 448 449 450 452 453 454455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 471 473 475476 477 479 482 483 485 486 487 488 489 490 491 495 496 498 498d 500 501502 503 504 507 510 514 515 516 517 518 525 526 527 528 529 530 531 532533 534 535 536 537 538 539 540 541 542 543 545 546 547 548 549 550 551552 553 554 556 557 558 559 560 563 565 568 569 570 571 574 575 577 578579 583 586 587 590 592 593 594 595 596 597 598 599 604c 605a 605b 605c605d 606 607 609 610 614 617 619 626 629 630 631 632 633a 633b 635 637638 639 640 642 644 645 646 650 654 656 662 663 664 665 666

Example C RSV Polymerase Inhibition Assay

Standard RSV polymerase assays were conducted in the presence of 10 nMrecombinant RSV complex in a reaction buffer containing Tris-HCl pH7.5,6 mM MgCl₂, and other additives and substrates including RNAoligonucleotides and radionucleotides. Standard reactions were incubatedin 96-well plate format for 2 h at 30° C., in the presence of increasingconcentration of inhibitor. The reaction was stopped with 90 μL of 0.1MEDTA, and the reaction product was transferred to a “reading” 96-wellplate. After washing of the plate, radiolabeled RNA products weredetected according to standard procedures with a Trilux Topcountscintillation counter. The compound concentration at which theenzyme-catalyzed rate was reduced by 50% (IC₅₀) was calculated byfitting the data to a non-linear regression (sigmoidal). The IC₅₀ valueswere derived from the mean of several independent experiments and areshown in Tables E and F.

Table E includes compounds with an IC₅₀ of <1 μM. Table F includescompounds with an IC₅₀<10 μM. Table G includes compounds with an IC₅₀value of <100 μM.

TABLE E Compound 101 115 116 116b 117 117b 118 118b 119 120 120b 122122a 123 125 126 127 128 130 140 141 142 143 147 166 167 176 179 181 182183 184 185 189 190 191 192 193 194 195 196 197 198 199 200 202 204 205207 208 209 210 211 212 213 214 215 217 218 219 221 220 222 223 224 225226 227 228 232 233 234 235 236 237 238 239 240 241 243 244 245 246 248249 250 251 252 254 255 256 257 258 259 260 261 262 263 264 266 267 270271 272 273 274 275 276 278 279 280 281 282 283 284 285 287 289 292 297298 299 301 302 303 304 305 306 307 308 309 310 311 312 314 315 316 317318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335336 337 338 339 340 341 342 343 344 345 346 347 348 349 353 354 355 356357 358 359 360 361 362 364 365 366 367 369 370 371 372 373 375 376 378379 380 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398399 400 402 403 405 406 409 411 413 415 418 419 421 423 424 425 428 431432 434 435 436 437 440 442 443 444 445 447 448 449 451 452 453 454 455456 459 460 461 462 463 464 465 466 467 469 470 473 474 475 476 479 481482 483 485 486 487 488 489 491 493 494 495 496 497 498 498c 498d 499500 501 501 502 503 504 505 506 507 508 509 510 511 514 515 516 517 518519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536537 538 539 540 541 452 543 545 546 547 548 549 550 551 552 553 554 555556 557 558 559 560 562 563 565 567 568 569 570 571 573 574 575 576 577578 579 580 581 582 583 584 585 586 588 589 590 591 593 594 595 596 598599 600 601 602 603 604d 605a 605c 605d 610 611 612 614 615 617 618 619620 621 622 623b 624b 625 626 627 628 629 630 631 632 633a 633b 634 635636 637 638 639 640 641 642 643 644 645 646 647 648 650 651 652 653 654655 656 657 658 662 663 664 665 666 667 668 669 676

TABLE F Compound 109 114 120a 122b 124 145 146 148 149 150 151 153 154165 168 174 175 177 187 188 203 216 247 253 265 268 277 286 290 294 296300 313 350 352 363 377 404 416 417 426 438 450 471 477 478 480 484 490492 498b 512 513 561 564 572 592 597 604a 604b 604c 607 608 609 613 616623a 624a 659 660 672 673

TABLE G Compound 116a 117a 118a 135 144 161 178 180 186 201 230 242 295368 382 407 408 412 420 422 427 430 439 441 446

Example D RSV Assay

The RSV sub genomic replicon 395 HeLa and APC126 were licensed fromApath (Brooklyn, N.Y.) and were originally developed by Dr. Mark Meeplesof Center for Vaccines & Immunity, the Research Institute at NationwideChildren's Hospital in Columbus, Ohio. To generate subgenomic RSVreplicon, three glycoprotein genes, those for SH, G, and F, from afull-length recombinant GFP-expressing (rg) RSV antigenomic cDNA weredeleted. In their place, a blasticidin S deaminase (bsd) gene wasinserted. Through multiple steps, the RSV replicon was established inHeLa cells (395 Hela) or BHK cells (APC126). Both 395 HeLa and APC126cells were cultured in Dulbecco's Modified Eagle Medium (DMEM)containing 4500 mg/L D-glucose, L-glutamine, and 110 mg/L sodiumpyruvate (Invitrogen, Cat. #11995-040). The medium was furthersupplemented with 10% (v/v) fetal bovine serum (FBS) (Mediatech, Cat.#35-010-CV), 1% (v/v) penicillin/streptomycin (Mediatech, Cat.#30-002-CI), and 10 μg/mL of Blasticidin (BSD) (Invivogen, Cat. codeant-bl-1). Cells were maintained at 37° C. in a humidified 5% CO₂atmosphere.

Determination of 50% inhibitory concentration (EC₅₀), 90% inhibitoryconcentration (EC₉₀) and 50% cytotoxic concentration (CC₅₀) in RSVreplicon cells were performed by the following procedure. On the firstday, 5000 RSV replicon cells per well were plated in a 96-well plate. Onthe following day, compounds to be tested were solubilized in 100% DMSOto 100× the desired final testing concentration. Each compound wasserially diluted (1:3) up to 9 distinct concentrations. Compounds in100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cellculture media. A 10 μL sample of the compounds diluted to 10% (v/v) DMSOwith cell culture media was used to treat the RSV replicon cells in96-well format. The final DMSO concentration was 1% (v/v). Cells wereincubated with compounds for 7 days (for 395Hela) or 3 days (for APC126)at 37° C. in a 5% CO₂ atmosphere. In each assay, positive control thatwas previously characterized in the RSV replicon assay was included.

The Renilla Luciferase Assay System (Promega, Cat. #E2820) was used tomeasure anti-RSV replicon activity. Assay plates were set up as statedabove. Luminescence was recorded using a Perkin Elmer multilabel counterVictor3V. EC₅₀, the concentration of the drug required for reducing RSVreplicon RNA by 50% in relation to the untreated cell control value, wascalculated from the plot of percentage reductions of the optical density(OD) value against the drug concentrations using the Microsoft Excelforecast function.

395 HeLa or APC126 cell proliferation assay (Promega; CellTiter-GloLuminescent Cell Viability Assay, Cat. #G7572) was used to measure cellviability. The CellTiter-Glo® Luminescent Cell Viability Assay is ahomogeneous method to determine the number of viable cells in culturebased on quantitation of the ATP present, which signals the presence ofmetabolically active cells. Assay plates were set up in the same formatas noted above for the replicon assay. CellTiter-Glo reagent (100 μL)was added to each well and incubated at room temperature for 8 minutes.Luminescence was recorded using a Perkin Elmer multilabel counterVictor3V. The CC₅₀, the concentration of the drug required for reducingviable cells by 50% in relation to the untreated cell control value, wascalculated from the plot of percentage reductions of the luminescencevalue against the drug concentrations using the Microsoft Excel forecastfunction.

Table H includes compounds with an EC₅₀ value that is less than 1 μM.Table I includes compounds with an EC₅₀ value that is equal to or higherthan 1 μM and less than 50 μM. Other tested compounds disclosed hereinhad an EC₅₀ value of 50 μM or greater.

TABLE H Compound 106 115 116 116b 117 117b 118 118b 119 120 120b 122122a 123 124 125 126 130 140 141 143 147 166 176 184 189 191 192 193 194195 198 200 202 204 205 208 209 211 218 223 224 226 228 232 237 239 240241 243 244 245 246 248 249 250 255 260 271 272 273 275 281 282 283 284289 292 298 302 303 304 306 307 308 309 310 311 312 314 315 316 317 318319 320 321 322 323 324 325 326 327 328 330 331 333 334 335 336 338 339341 342 343 344 345 346 347 348 349 354 355 356 357 358 359 360 361 362363 364 365 366 369 370 371 372 373 376 379 380 383 384 385 386 387 388389 390 391 392 393 394 395 396 397 398 400 403 405 406 409 411 413 415418 419 421 423 424 425 428 431 434 436 437 442 443 444 445 447 448 449452 453 454 455 456 459 460 462 466 467 470 483 485 486 487 488 489 490491 493 494 496 497 498 498d 499 500 501 502 503 504 505 506 507 508 509510 511 514 515 516 519 520 521 523 524 525 526 527 528 529 530 531 532533 534 535 536 538 539 540 542 543 545 546 547 548 550 551 552 554 555556 558 560 561 562 563 564 567 569 571 572 574 575 576 577 578 579 580581 583 584 585 586 588 589 590 594 595 596 598 600 601 602 603 604d605d 611 612 614 615 621 622 623b 624b 626 627 630 633b 634 635 636 637638 640 641 642 643 644 645 646 647 650 651 653 659 663 664 665 667 672675

TABLE I Compound 127 128 163 168 220 313 332 375 378 438 461

Example 15 Combination Studies

RSV with Renilla Reporter

RSV expressing Renilla luciferase (A2-RL-line19F) was generated by Dr.Martin Moore of Emory University, Atlanta, Ga., USA. The in vitro viralkinetics of A2-RL-line19F is similar to that of wild type RSV (SeeHotard, A. L., Virology (2012) 434(1): 129-136).

Host cell HEp-2 was purchased from ATCC (Cat. #CCL-23) and cells werecultured in DMEM/Ham's F-12 50/50 1× containing L-glutamine and 15 mMHEPES (Mediatech, Cat. #10-092-CM). The medium was further supplementedwith 5% (v/v) FBS (Mediatech, Cat. #35-010-CV) and 1% (v/v)penicillin/streptomycin (Mediatech, Cat. #30-002-CI). HEp-2 cells weremaintained at 37° C. in a humidified 5% CO₂ atmosphere.

Drug Treatment and Viral Dosing

To determine the effect of a combination of compounds, the followingprocedure was followed. On the first day, 20,000 HEp-2 cells were platedper well in a 96-well plate. On the following day, test articles weresolubilized in 100% DMSO (for chemicals) or 1×PBS (for biologies) to200× the desired final testing concentration. Subsequently, Compound(A), or a pharmaceutically acceptable salt thereof, was serially diluted(1:3) to 9 distinct concentrations “horizontally” in a 96-well plate,and Compound (B), or a pharmaceutically acceptable salt thereof, wasserially diluted (1:3) to 7 distinct concentrations “vertically” in96-well plate. The serially diluted 200× test articles were then diluted1:10 into cell culture media to generate 20× test articles. A 5 μLaliquot of the 20× test articles was added in a checkerboard fashion tothe cells with 90 μL existing media. Space was also allotted fortitrations of each of the compounds alone to be used as referencecontrols. After 12 hour pre-incubation of test articles, A2-RL-line19Fat an MOI of 0.5 was added to the plate and further incubated for 2 daysat 37° C. in a 5% CO₂.

Determination of Anti-RSY Activity

The Renilla Luciferase Assay System (Promega, Cat. #E2820) was used tomeasure anti-RSV replicon activity. Assay plates were set up as statedabove. Luminescence was recorded using a Perkin Elmer multilabel counterVictor3V.

Cell Viability Assay

Promega CellTiter-Glo Luminescent Cell Viability Assay, Cat. #G7572) wasused to measure cell viability. The CellTiter-Glo® Luminescent CellViability Assay is a homogeneous method to determine the number ofviable cells in culture based on quantitation of the adenosinetriphosphate (ATP) present, which signals the presence of metabolicallyactive cells. Assay plates were set up in the same format the anti-RSVassay, except that no virus was added to the cell viability assay. A100-μL aliquot of CellTiter-Glo reagent was added to each well andincubated at room temperature for 8 minutes. Luminescence was recordedusing a Perkin Elmer multilabel counter Victor3V.

Data Analysis

Each experiment was performed at N=5 for both anti-RSV activity and cellviability. Mean percent inhibition of the replicon values from the 5experiments was generated and for anti-RSV activity, it was analyzedusing two drug interaction analysis models, Isobologram Analysis and/orPrichard's Model.

Isobologram Analysis

The effects of drug-drug combinations were evaluated by the Loeweadditivity model in which the experimental data were analyzed usingCalcuSyn (Biosoft, Ferguson, Mo.), a computer program based on themethod of Chou and Talalay. The combination index (CI) value and theisobologram for each experimental combination were calculated. CI valuesof <1, 1, and >1 indicate synergy, additive effect, and antagonism,respectively. Under the synergy category, CI<0.1 is considered verystrong synergism; CI 0.1-0.3 strong synergism; CI 0.3-0.7 synergism andCI 0.7-0.85 moderate synergism. The isobologram analysis, whichgraphically represents additive, synergistic, and antagonistic drugeffects, was also used to model the interaction of antiviral activities.In this representation, an effective concentration (EC) value of onedrug is plotted on one axis and corresponding EC value of a second drugis plotted on the second axis; the line connecting these two pointsrepresents the amount of each drug in a combination that would berequired to reach the equivalent EC value, given that their effects areadditive.

Prichard's Model (MacSynergy II)

MacSynergy II software was kindly provided by Dr. M. Prichard(University of Michigan). This program allows the three-dimensionalexamination of drug interactions of all data points generated from thecheckerboard combination of two inhibitors with Bliss-Independencemodel. Confidence bounds are determined from replicate data. If the 95%confidence limits (CL) do not overlap the theoretic additive surface,then the interaction between the two drugs differs significantly fromadditive. The volumes of synergy or antagonism can be determined andgraphically depicted in three dimensions and represent the relativequantity of synergism or antagonism per change in the two drugconcentrations. Synergy and antagonism volumes are based on the Blissindependence model, which assumes that both compounds act independentlyon different targets. A set of predicted fractional responses faAB underthe Bliss independence model is calculated as faAB=faA+faB−faA·faB withfaA and faB representing the fraction of possible responses, e.g. %inhibition, of compounds A and B at amounts dA and dB, respectively, anddescribes the % inhibition of a combination of compounds A and B atamount (dA+dB). If faAB>faA+faB−faA·faB then we have Bliss synergy; iffaAB<faA+faB−faA·faB then we have Bliss antagonism. The 95%synergy/antagonism volumes are the summation of the differences betweenthe observed inhibition and the 95% confidence limit on the predictionof faAB under the Bliss independence model. MacSynergy II was used fordata analysis.

MacSynergy II Volume Descriptions: <25 μM²%=Additive; 25-50 μM²%=Minorsynergism; 50-100 μM²%=Significant synergism; and >100 μM²%=Strongsynergism. For the combination of 574 and BMS-433771 (a fusion proteininhibitor) had a synergy volume of 24.9 μM²% (additive/minor synergism).

Example F Parainfluenza Virus-3 (PIV-3) Plaque Assay

MA-104 cells are grown in 24-well plates to a confluency of 90% in thepresence of minimal essential medium (MEM) supplemented with 10% fetalbovine serum and antibiotics (C-EMEM). The cells are then washed twicewith non-complete minimal essential medium (NC-EMEM). Test articles aredissolved in DMSO to a stock concentration of 10 mM.

An aliquot of 0.5 mL of the test article at various concentrations arethen inoculated in triplicate wells and are incubated for 60 mins at 37°C. with 5% CO₂ for the diffusion of test article into MA-104 cells.After the incubation period, a stock of human PIV type 3 are thawed anddiluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. Analiquot of 0.1 mL are then inoculated into all the wells except for thenegative and test article toxicity control wells. Upon infection, theplates are incubated for 72 h at 37° C. at 5% CO₂. After incubation, theplates are examined under microscopy to record cytotoxicity. Thesupernatants are collected for viral quantification using a standardplaque assay using MA-104 cells as the indicator cells.

To perform the plaques assay, MA-104 cells are grown to confluence in24-well plates. The cells are washed with serum-free medium prior toinoculation of duplicate wells with serial 10-fold dilutions ofsupernatant sample. After 1 h incubation at 37° C., the samples areaspirated and 1.0 mL of methyl cellulose overlay media are added to eachwell. After 6 days of culture, the cells are fixed and stained with0.06% crystal violet in 1% glutaraldehyde and viral plaques areenumerated. The data are analyzed with Prism software with EC₅₀ definedas drug concentration that reduced the viral load 50% from the viralcontrol (VC).

Example G Human Metapneumovirus (hMPV) TCID₅₀ Assay

LLC-MK2 cells are grown in 24-well plates to a confluency of 90% in thepresence of minimal essential medium (MEM) supplemented with 10% fetalbovine serum and antibiotics (C-EMEM). The cells are then washed twicewith non-complete minimal essential medium (NC-EMEM). Test articles aredissolved in DMSO to a stock concentration of 10 mM.

An aliquot of 0.5 mL of the test article at various concentrations arethen inoculated in triplicate wells and are incubated for 60 mins at 37°C. with 5% CO₂ for the diffusion of test article into LLC-MK2 cells.After the incubation period, a stock of human metapneumovirus are thawedand diluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL.An aliquot of 0.1 mL are then inoculated into all the wells except forthe negative and test article toxicity control wells. Upon infection,the plates are incubated for 7 days at 37° C. at 5% CO₂. Afterincubation, the plates are examined under microscopy to recordcytotoxicity. The supernatants are collected for viral quantificationusing a standard TCID₅₀ assay using LLC-MK2 cells as the indicatorcells. The data are analyzed with Prism software with EC₅₀ defined asdrug concentration that reduced the viral load 50% from the viralcontrol (VC).

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it will be understood by those of skill in the art thatnumerous and various modifications can be made without departing fromthe spirit of the present disclosure. Therefore, it should be clearlyunderstood that the forms disclosed herein are illustrative only and arenot intended to limit the scope of the present disclosure, but rather toalso cover all modification and alternatives coming with the true scopeand spirit of the invention.

1. A compound of Formula (I) having the structure:A-L-Y  (I), or a pharmaceutically acceptable salt thereof, wherein: L isselected from the group consisting of:

A is selected from the group consisting of an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted aryl, an optionally substituted aryl (C₁₋₂ alkyl), anoptionally substituted heteroaryl, and an optionally substitutedheterocyclyl; Y is selected from the group consisting of an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl, andan optionally substituted heterocyclyl; R^(1a), R^(1b), R^(1c), andR^(1d) are each independently hydrogen or an unsubstituted C₁₋₄ alkyl;R^(2a), R^(2a1), R^(2b), R^(2b1), R^(2c), R^(2c1), R^(2d), and R^(2d1)are each independently selected from the group consisting of hydrogen,an optionally substituted C₁₋₄ alkyl, an optionally substitutedaryl(C₁₋₆ alkyl), an optionally substituted heterocyclyl(C₁₋₆ alkyl), analkoxyalkyl, an aminoalkyl, a hydroxyalkyl, and hydroxy; or R^(2a1) ishydrogen, and R^(1a) and R^(2a) are joined together with the atoms towhich they are attached to form an optionally substituted 5-memberedheterocyclyl or an optionally substituted 6-membered heterocyclyl,R^(2b1) is hydrogen, and R^(1b) and R^(2b) are joined together with theatoms to which they are attached to form an optionally substituted5-membered heterocyclyl or an optionally substituted 6-memberedheterocyclyl;

between X^(1a) and X^(2a) represents a single or double bond betweenX^(1a) and X^(2a);

between X^(2a) and X^(3a) represents a single or double bond betweenX^(2a) and X^(3a); provided that

between X^(1a) and X^(2a) and

between X^(2a) and X^(3a) cannot be both double; X^(1a), X^(2a), andX^(3a) are each independently C, N, O, or C(═O), and form a ring or ringsystem selected from an optionally substituted aryl, an optionallysubstituted heteroaryl and an optionally substituted heterocyclyl byjoining X^(1a) and X^(3a) together; with the proviso that the valenciesof X^(1a), X^(2a), and X^(3a) can be each independently satisfied with asubstituent selected from hydrogen and an optionally substituted C₁₋₄alkyl, and X^(1a), X^(2a), and X^(3a) are uncharged; R^(3a) and R^(3a1)are each independently selected from the group consisting of hydrogen,hydroxy, halogen, amino, an optionally substituted C₁₋₄ alkyl, anoptionally substituted C₂₋₄ alkenyl, an optionally substituted C₂₋₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₁₋₄ alkoxy, —O-carboxy, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, CHF₂, CF₃, and

provided that R^(3a) and R^(3a1) cannot be both hydrogen; or R^(3a) andR^(3a1) together form ═N—OR^(a); or R^(3a) and R^(3a1) together with theatom to which they are attached can be joined to form an optionallysubstituted 3 membered ring, an optionally substituted 4 membered ring,an optionally substituted 5 membered ring or an optionally substituted 6membered ring; R^(4a), R^(4a1), R^(4a2), and R^(4a3) are eachindependently hydrogen or an unsubstituted C₁₋₄ alkyl; R^(5a) andR^(5a1) are each independently hydrogen or an unsubstituted C₁₋₄ alkyl;R^(6a) and R^(6a1) are each independently hydrogen, an optionallysubstituted C₁₋₄ alkyl, or an optionally substituted alkoxyalkyl;R^(6a2) and R^(6a3) are each independently hydrogen or an unsubstitutedC₁₋₄ alkyl; X^(1b), X^(2b), and X^(3b) form a bi-cyclic ring selectedfrom an optionally substituted bi-cyclic heteroaryl and an optionallysubstituted bi-cyclic heterocyclyl by joining X^(1b) and X^(3b)together, wherein (i) X^(1b) is C, X^(2b) is N, and X^(3b) is C, (ii)X^(1b) is N, X^(2b) is N, and X^(3b) is C, (iii) X^(1b) is N, X^(2b) isC(═O), and X^(3b) is N, or (iv) X^(1b) is C, X^(2b) is O, and X^(3b) isC, and wherein

between X^(1b) and X^(2b) represents a single or double bond betweenX^(1b) and X^(2b);

between X^(2b) and X^(3b) represents a single or double bond betweenX^(2b) and X^(3b); and provided that both

cannot be double bonds; with the proviso that the valencies of X^(1b),X^(2b), and X^(3b) can be each independently satisfied with asubstituent selected from hydrogen and an optionally substituted C₁₋₄alkyl; and X^(1b), X^(2b), and X^(3b) are uncharged; R^(3c) and R^(3c1)are each independently selected from the group consisting of hydrogen,hydroxy, halogen, amino, an optionally substituted C₁₋₄ alkyl, anoptionally substituted C₂₋₄ alkenyl, an optionally substituted C₂₋₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₁₋₄ alkoxy, —O-carboxy, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, CHF₂, CF₃, and

provided that R^(3c) and R^(3c1) cannot be both hydrogen; or R^(3c) andR^(3c1) together form ═N—OR^(c); or R^(3c) and R^(3c1) together with theatom to which they are attached can be joined to form an optionallysubstituted 3 membered ring, an optionally substituted 4 membered ring,an optionally substituted 5 membered ring, or an optionally substituted6 membered ring; R^(a) and R^(c) are each independently hydrogen or anunsubstituted C₁₋₄ alkyl; R^(4c) and R^(5c) are taken together to forman unsubstituted aryl, an unsubstituted heteroaryl, or an optionallysubstituted heterocyclyl; Z^(c) is N or CH; m^(d) is 0 or 1; and ringB^(d) is an optionally substituted C₅ cycloalkyl; ring B^(d1) is anoptionally substituted pyridinyl; and provided that when L is Formula(Ic), then Y is absent; and provided that the compound is not

2-143. (canceled)
 144. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L is

and wherein R^(7a1), R^(7a2), and R^(7a3) are each independentlyselected from the group consisting of hydrogen, halogen, hydroxy, anoptionally substituted C₁₋₈ alkyl, an optionally substituted C₂₋₈alkenyl, an optionally substituted C₂₋₈ alkynyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutedheterocyclyl, an optionally substituted hydroxyalkyl, an optionallysubstituted C₁₋₈ alkoxy, an optionally substituted alkoxyalkyl, amino,mono-substituted amino, di-substituted amino, halo(C₁₋₈ alkyl),haloalkyl, an optionally substituted O-amido, and an optionallysubstituted C-carboxy.
 145. The compound of claim 144, wherein thecompound is

or a pharmaceutically acceptable salt of any of the foregoing.
 146. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L is


147. The compound of claim 146, wherein A is an optionally substitutedphenyl and Y is an optionally substituted benzothiophenyl or anoptionally substituted phenyl.
 148. The compound of claim 146, whereinthe compound is

or a pharmaceutically acceptable salt of any of the foregoing.
 149. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L is


150. The compound of claim 149, wherein X^(1b), X^(2b), and X^(3b) forman optionally substituted


151. The compound of claim 149, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 152. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein L is


153. The compound of claim 152, wherein the compound is

or a pharmaceutically acceptable salt of any of the foregoing.
 154. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L is


155. The compound of claim 154, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 156. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein L is

wherein: the dashed semi-circle along with the two carbon atoms to whichit is connected form an optionally substituted cycloalkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, or an optionallysubstituted heterocyclyl; and R^(8a3) is hydrogen, halogen, hydroxy, anoptionally substituted C₁₋₈ alkyl, an optionally substituted C₂₋₈alkenyl, an optionally substituted C₂₋₈ alkynyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutedheterocyclyl, an optionally substituted hydroxyalkyl, an optionallysubstituted C₁₋₈ alkoxy, an optionally substituted alkoxyalkyl, amino,mono-substituted amino, di-substituted amino, halo(C₁₋₈ alkyl),haloalkyl, or an optionally substituted C-carboxy.
 157. The compound ofclaim 156, wherein the compound is

or a pharmaceutically acceptable salt of any of the foregoing.
 158. Apharmaceutical composition comprising an effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, diluent, excipient, or combinationthereof.
 159. A method for ameliorating or treating a paramyxovirusinfection, the method comprising administering to a subject sufferingfrom the paramyxovirus infection an effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 160. A methodfor inhibiting replication of a paramyxovirus, the method comprisingcontacting a cell infected with the paramyxovirus with an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 161. The method of claim 159, wherein the paramyxovirusinfection is a human respiratory syncytial virus infection.
 162. Themethod of claim 159, further comprising administering to the subject oneor more agents.
 163. The method of claim 162, wherein the paramyxovirusinfection is a human respiratory syncytial virus infection; and whereinthe one or more agents is selected from the group consisting of ananti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, aRSV polymerase inhibitor, an IMPDH inhibitor, an interferon, any othercompound that inhibits the RSV virus, and pharmaceutically acceptablesalts of any of the foregoing.
 164. The method of claim 162, wherein theone or more agents is selected from the group consisting of RSV-IGIV,palivizumab, motavizumab,1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one(BMS-433771),4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic-acid(RFI-641),4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonicacid, disodium salt (CL387626),2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol(JNJ-2408068),2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol(TMC-353121),5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol(VP-14637, MDT-637),N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide(P13),2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol(R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (C15),(R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[1′,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one(BTA9981),[2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate(MBX-300), BTA-C286,N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide(GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor (such as apeptide having the sequence DEFDASISQVNEKINQSLAFIRKSDELL (T-67), apeptide having the sequence FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-118),(S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea(RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl)amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide(YM-53403).N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido)benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide.6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide,4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione,AZ27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide(EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide(pyrazofurin),1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide(Taribavirin, viramidine), 1,3,4-thiadiazol-2-ylcyanamide (LY253963),tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate(VX-497),(4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoicacid (Mycophenolic acid),2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate(Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, aType 3 interferon, a double stranded RNA oligonucleotide,5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide(leflumomide),N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide(JMN3-003), an intratracheal formulation of recombinant human CC10(CG-100), high titer, human immunoglobulin (RI-001), a non-neutralizingmAb against the G protein (mAb 131-2G), ALN-RSV01, ALN-RSV02, Medi-559,Medi-534, Medi-557, and pharmaceutically acceptable salts of any of theforegoing.